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DNA methylation and type 2 diabetes: a systematic review

DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid early detection and/or therapeutic treatm...

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Machine learning unveils an immune-related DNA methylation profile in germline DNA from breast cancer patients

There is an unmet need for precise biomarkers for early non-invasive breast cancer detection. Here, we aimed to identify blood-based DNA methylation biomarkers that are associated with breast cancer.

DNA methylation signatures of youth-onset type 2 diabetes and exposure to maternal diabetes

Youth-onset type 2 diabetes (T2D) is physiologically distinct from adult-onset, but it is not clear how the two diseases differ at a molecular level. In utero exposure to maternal type 2 diabetes (T2D) is know...

Hyper-physiologic mechanical cues, as an osteoarthritis disease-relevant environmental perturbation, cause a critical shift in set points of methylation at transcriptionally active CpG sites in neo-cartilage organoids

Osteoarthritis (OA) is a complex, age-related multifactorial degenerative disease of diarthrodial joints marked by impaired mobility, joint stiffness, pain, and a significant decrease in quality of life. Among...

Decitabine as epigenetic priming with CLAG induce improved outcome of relapsed or refractory acute myeloid leukemia in children

Decitabine (DAC), a DNA methyltransferase inhibitor, has shown efficacy combined with chemotherapy for relapsed or refractory (R/R) acute myeloid leukemia (AML) in adults, but less is known about its efficacy ...

Novel 14q32.2 paternal deletion encompassing the whole DLK1 gene associated with Temple syndrome

Temple syndrome (TS14) is a rare imprinting disorder caused by maternal UPD14, imprinting defects or paternal microdeletions which lead to an increase in the maternal expressed genes and a silencing the patern...

Epigenetics of the non-coding RNA nc886 across blood, adipose tissue and skeletal muscle in offspring exposed to diabetes in pregnancy

Diabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially...

Genome- and epigenome-wide association studies identify susceptibility of CpG sites and regions for metabolic syndrome in a Korean population

While multiple studies have investigated the relationship between metabolic syndrome (MetS) and its related traits (fasting glucose, triglyceride, HDL cholesterol, blood pressure, waist circumference) and DNA ...

Correction: Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age

The original article was published in Clinical Epigenetics 2024 16 :35

DNA methylation of imprint control regions associated with Alzheimer’s disease in non-Hispanic Blacks and non-Hispanic Whites

Alzheimer’s disease (AD) prevalence is twice as high in non-Hispanic Blacks (NHBs) as in non-Hispanic Whites (NHWs). The objective of this study was to determine whether aberrant methylation at imprint control...

Evaluating the link between DIO3 -FA27 promoter methylation, biochemical indices, and heart failure progression

Heart failure (HF) is a disease that poses a serious threat to individual health, and DNA methylation is an important mechanism in epigenetics, and its role in the occurrence and development of the disease has...

Discovery and technical validation of high-performance methylated DNA markers for the detection of cervical lesions at risk of malignant progression in low- and middle-income countries

Cervical cancer remains a leading cause of death, particularly in developing countries. WHO screening guidelines recommend human papilloma virus (HPV) detection as a means to identify women at risk of developi...

DNMT1/miR-152-3p/SOS1 signaling axis promotes self-renewal and tumor growth of cancer stem-like cells derived from non-small cell lung cancer

CSLCs(Cancer stem cell-like cells), which are central to tumorigenesis, are intrinsically influenced by epigenetic modifications. This study aimed to elucidate the underlying mechanism involving the DNMT1/miR-...

Polycomb repressive complex 2 and its core component EZH2: potential targeted therapeutic strategies for head and neck squamous cell carcinoma

The polycomb group (PcG) comprises a set of proteins that exert epigenetic regulatory effects and play crucial roles in diverse biological processes, ranging from pluripotency and development to carcinogenesis...

Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk

The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging...

Epigenetics in diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is a critical complication that poses a significant threat to the health of patients with diabetes. The intricate pathological mechanisms of DCM cause diastolic dysfunction, follo...

Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer

The intriguing connection between selenium and cancer resembles a captivating puzzle that keeps researchers engaged and curious. While selenium has shown promise in reducing cancer risks through supplementatio...

Nucleosome reorganisation in breast cancer tissues

Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also ...

Refining risk prediction in pediatric acute lymphoblastic leukemia through DNA methylation profiling

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, and despite considerable progress in treatment outcomes, relapses still pose significant risks of mortality and long-term complicati...

Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2: miR-182 promoter methylation is a predictive marker for hypomethylation agents + BCL2 inhibitor venetoclax

miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells hav...

Head and neck cancer of unknown primary: unveiling primary tumor sites through machine learning on DNA methylation profiles

The unknown tissue of origin in head and neck cancer of unknown primary (hnCUP) leads to invasive diagnostic procedures and unspecific and potentially inefficient treatment options for patients. The most commo...

Epigenetic scores of blood-based proteins as biomarkers of general cognitive function and brain health

Epigenetic Scores (EpiScores) for blood protein levels have been associated with disease outcomes and measures of brain health, highlighting their potential usefulness as clinical biomarkers. They are typicall...

A validated restriction enzyme ddPCR cg05575921 ( AHRR ) assay to accurately assess smoking exposure

In this study, a novel restriction enzyme (RE) digestion-based droplet digital polymerase chain reaction (ddPCR) assay was designed for cg005575921 within the AHRR gene body and compared with matching results obt...

Mother adversity and co-residence time impact mother–child similarity in genome-wide and gene-specific methylation profiles

The effects of adverse life events on physical and psychological health, with DNA methylation (DNAm) as a critical underlying mechanism, have been extensively studied. However, the epigenetic resemblance betwe...

Correction: Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease

The original article was published in Clinical Epigenetics 2024 16 :28

Identification of miR-20b-5p as an inhibitory regulator in cardiac differentiation via TET2 and DNA hydroxymethylation

Congenital heart disease (CHD) is a prevalent congenital cardiac malformation, which lacks effective early biological diagnosis and intervention. MicroRNAs, as epigenetic regulators of cardiac development, pro...

Epigenetic age acceleration and risk of aortic valve stenosis: a bidirectional Mendelian randomization study

Aortic valve stenosis (AVS) is the most prevalent cardiac valve lesion in developed countries, and pathogenesis is closely related to aging. DNA methylation-based epigenetic clock is now recognized as highly a...

MAL expression downregulation through suppressive H3K27me3 marks at the promoter in HPV16-related cervical cancers is prognostically relevant and manifested by the interplay of novel MAL antisense long noncoding RNA AC103563.8, E7 oncoprotein and EZH2

MAL (T-lymphocyte maturation-associated protein) is highly downregulated in most cancers, including cervical cancer (CaCx), attributable to promoter hypermethylation. Long noncoding RNA genes (lncGs) play pivo...

Novel histone post-translational modifications in Alzheimer’s disease: current advances and implications

Alzheimer’s disease (AD) has a complex pathogenesis, and multiple studies have indicated that histone post-translational modifications, especially acetylation, play a significant role in it. With the developme...

An EWAS of dementia biomarkers and their associations with age, African ancestry, and PTSD

Large-scale cohort and epidemiological studies suggest that PTSD confers risk for dementia in later life but the biological mechanisms underlying this association remain unknown. This study examined this quest...

Cell-free DNA methylation reveals cell-specific tissue injury and correlates with disease severity and patient outcomes in COVID-19

The recently identified methylation patterns specific to cell type allows the tracing of cell death dynamics at the cellular level in health and diseases. This study used COVID-19 as a disease model to investi...

DNA methylation may partly explain psychotropic drug-induced metabolic side effects: results from a prospective 1-month observational study

Metabolic side effects of psychotropic medications are a major drawback to patients’ successful treatment. Using an epigenome-wide approach, we aimed to investigate DNA methylation changes occurring secondary ...

Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age

We previously reported in the “Vitamin C to Decrease the Effects of Smoking in Pregnancy on Infant Lung Function” randomized clinical trial (RCT) that vitamin C (500 mg/day) supplementation to pregnant smokers...

The Correction to this article has been published in Clinical Epigenetics 2024 16 :59

Prediction of methylation status using WGS data of plasma cfDNA for multi-cancer early detection (MCED)

Cell-free DNA (cfDNA) contains a large amount of molecular information that can be used for multi-cancer early detection (MCED), including changes in epigenetic status of cfDNA, such as cfDNA fragmentation pro...

Reduced representative methylome profiling of cell-free DNA for breast cancer detection

Whole-genome methylation sequencing of cfDNA is not cost-effective for tumor detection. Here, we introduce reduced representative methylome profiling (RRMP), which employs restriction enzyme for depletion of A...

Epigenetic aging in older people living with HIV in Eswatini: a pilot study of HIV and lifestyle factors and epigenetic aging

People living with HIV (PLHIV) on effective antiretroviral therapy are living near-normal lives. Although they are less susceptible to AIDS-related complications, they remain highly vulnerable to non-communica...

Abnormal DNA methylation within HPA-axis genes years after paediatric critical illness

Critically ill children suffer from impaired physical/neurocognitive development 2 years later. Glucocorticoid treatment alters DNA methylation within the hypothalamus–pituitary–adrenal (HPA) axis which may im...

Epigenetic regulation and factors that influence the effect of iPSCs-derived neural stem/progenitor cells (NS/PCs) in the treatment of spinal cord injury

Spinal cord injury (SCI) is a severe neurological disorder that causes neurological impairment and disability. Neural stem/progenitor cells (NS/PCs) derived from induced pluripotent stem cells (iPSCs) represen...

Epigenome-wide association study of dietary fatty acid intake

Dietary intake of n-3 polyunsaturated fatty acids (PUFA) may have a protective effect on the development of cardiovascular diseases, diabetes, depression and cancer, while a high intake of n-6 PUFA was often r...

Increased CpG methylation at the CDH1 locus in inflamed ileal mucosa of patients with Crohn disease

E-cadherin, a major actor of cell adhesion in the intestinal barrier, is encoded by the CDH1 gene associated with susceptibility to Crohn Disease (CD) and colorectal cancer. Since epigenetic mechanisms are suspec...

The Correction to this article has been published in Clinical Epigenetics 2024 16 :43

Kidney-specific methylation patterns correlate with kidney function and are lost upon kidney disease progression

Chronological and biological age correlate with DNA methylation levels at specific sites in the genome. Linear combinations of multiple methylation sites, termed epigenetic clocks, can inform us the chronologi...

Molecular map of disulfidptosis-related genes in lung adenocarcinoma: the perspective toward immune microenvironment and prognosis

Disulfidptosis is a recently discovered form of programmed cell death that could impact cancer development. Nevertheless, the prognostic significance of disulfidptosis-related genes (DRGs) in lung adenocarcino...

Tissue of origin prediction for cancer of unknown primary using a targeted methylation sequencing panel

Cancer of unknown primary (CUP) is a group of rare malignancies with poor prognosis and unidentifiable tissue-of-origin. Distinct DNA methylation patterns in different tissues and cancer types enable the ident...

The interaction between DNA methylation and tumor immune microenvironment: from the laboratory to clinical applications

DNA methylation is a pivotal epigenetic modification that affects gene expression. Tumor immune microenvironment (TIME) comprises diverse immune cells and stromal components, creating a complex landscape that ...

Correction: A transgenic mice model of retinopathy of cblG‑type inherited disorder of one‑carbon metabolism highlights epigenome‑wide alterations related to cone photoreceptor cells development and retinal metabolism

The original article was published in Clinical Epigenetics 2023 15 :158

Self-control is associated with health-relevant disparities in buccal DNA-methylation measures of biological aging in older adults

Self-control is a personality dimension that is associated with better physical health and a longer lifespan. Here, we examined (1) whether self-control is associated with buccal and saliva DNA-methylation (DN...

Per-cell histone acetylation is associated with terminal differentiation in human T cells

Epigenetic remodeling at effector gene loci has been reported to be critical in regulating T cell differentiation and function. However, efforts to investigate underlying epigenetic mechanisms that control T c...

Epigenetics of prenatal stress in humans: the current research landscape

Fetal exposure to prenatal stress can have significant consequences on short- and long-term health. Epigenetic mechanisms, especially DNA methylation (DNAm), are a possible process how these adverse environmen...

Identification of DNA methylation biomarkers for evaluating cardiovascular disease risk from epigenome profiles altered by low-dose ionizing radiation

Environmental exposure, medical diagnostic and therapeutic applications, and industrial utilization of radionuclides have prompted a growing focus on the risks associated with low-dose radiation (< 100 mGy). C...

METTL3 promotes osteoblast ribosome biogenesis and alleviates periodontitis

Periodontitis is a highly prevalent oral disease characterized by bacterium-induced periodontal inflammation and alveolar bone destruction. Osteoblast function is impaired in periodontitis with a global proteo...

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ISSN: 1868-7083 (electronic)

Clinical Epigenetics

ISSN: 1868-7083

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Broadening the epigenetic horizon of abiotic stress response in plants

Review Paper
Published: 11 May 2024

Cite this article

Himani Chhatwal 1 ,
Jogindra Naik 1 ,
Ashutosh Pandey 1 &
Prabodh Kumar Trivedi ORCID: orcid.org/0000-0001-6463-1731 2

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Plants, unlike animals, cannot move from one place to another and have to face different climatic disturbances wherever they are growing. So, they have innumerable built-in mechanisms to adapt to various abiotic stressful conditions like drought, heat, cold, and salinity. The changing environmental conditions influence the expression patterns of genes. Epigenetics involves heritable changes in DNA bases or histone proteins, which ultimately create different conformational states of chromatin. The regulatory enzymes of epigenetic modifications are grouped as writers, readers and erasers, which add, recognize and remove the epigenetic marks, respectively. Here, we provide a comprehensive overview of the mechanism of DNA methylation by the RdDM pathway, its maintenance and removal, and different histone modification categories like acetylation, methylation, phosphorylation and ubiquitination. This review further discusses in detail the crucial role these modifications play in adapting to major abiotic stresses and how plants preserve these experiences as stress memory to respond to recurring stresses. It emphasizes the role of epigenetic modifications as a crucial mechanism for building plant’s tolerance and how it can be an important research priority to improve plant growth and development under abiotic stress conditions.

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Drought Tolerance Strategies in Plants: A Mechanistic Approach

Drought Stress in Plants: An Overview

Nitrogen in plants: from nutrition to the modulation of abiotic stress adaptation

Abbreviations.

Chromomethylase

Domains rearranged methyltransferase 2

Methyltransferase 1

RNA-directed DNA methylation

Histone acetyltransferase

Histone deactylase

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Acknowledgements

This work was supported by the core grant of National Institute of Plant Genome Research and research grant from Department of Biotechnology (BT/PR36694/NNT/281722/2020) to AP. HC and JN acknowledge University Grants Commission and Council of Scientific and Industrial Research, Government of India for Junior and Senior Research Fellowships, respectively. PKT acknowledges Science and Engineering Research Board, New Delhi for JC Bose National Fellowship (JCB/2021/000036). The authors are thankful to DBT-eLibrary Consortium (DeLCON) for providing access to e-resources. CSIR-CIMAP Publication Number: CIMAP/PUB/ 2024/58.

Funding was provided by CIMAP (Grant No. JCB/2021/000036).

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Epigenetics and Child Development: How Children’s Experiences Affect Their Genes

For more information about epigenetics, please scroll down below the infographic .

New scientific research shows that environmental influences can actually affect whether and how genes are expressed. In fact, scientists have discovered that early experiences can determine how genes are turned on and off and even whether some are expressed at all. Thus, the old ideas that genes are “set in stone” or that they alone determine development have been disproven. Nature vs. Nurture is no longer a debate—it’s nearly always both!

More Information on Epigenetics Deep Dive: Gene-Environment Interaction Learn more about the physical and chemical processes that take place as part of the creation of the epigenome. Working Paper 10: Early Experiences Can Alter Gene Expression and Affect Long-Term Development This in-depth working paper explains how genes and the environment interact, and gives recommendations for ways that caregivers and policymakers can effectively respond to the science.

During development, the DNA that makes up our genes accumulates chemical marks that determine how much or little of the genes is expressed. This collection of chemical marks is known as the “ epigenome .” The different experiences children have rearrange those chemical marks. This explains why genetically identical twins can exhibit different behaviors, skills, health, and achievement.

Correcting Popular Misrepresentations of Science

Until recently, the influences of genes were thought to be set, and the effects of children’s experiences and environments on brain architecture and long-term physical and mental health outcomes remained a mystery. That lack of understanding led to several misleading conclusions about the degree to which negative and positive environmental factors and experiences can affect the developing fetus and young child. The following misconceptions are particularly important to set straight.

Contrary to popular belief, the genes inherited from one’s parents do not set a child’s future development in stone. Variations in DNA sequences between individuals certainly influence the way in which genes are expressed and how the proteins encoded by those genes will function. But that is only part of the story—the environment in which one develops , before and soon after birth, provides powerful experiences that chemically modify certain genes which, in turn, define how much and when they are expressed. Thus, while genetic factors exert potent influences, environmental factors have the ability to alter the genes that were inherited.
Although frequently misunderstood, adverse fetal and early childhood experiences can—and do—lead to physical and chemical changes in the brain that can last a lifetime. Injurious experiences , such as malnutrition, exposure to chemical toxins or drugs, and toxic stress before birth or in early childhood are not “forgotten,” but rather are built into the architecture of the developing brain through the epigenome. The “biological memories” associated with these epigenetic changes can affect multiple organ systems and increase the risk not only for poor physical and mental health outcomes but also for impairments in future learning capacity and behavior.
Despite some marketing claims to the contrary, the ability of so-called enrichment programs to enhance otherwise healthy brain development is not known. While parents and policymakers might hope that playing Mozart recordings to newborns will produce epigenetic changes that enhance cognitive development, there is absolutely no scientific evidence that such exposure will shape the epigenome or enhance brain function. What research has shown is that specific epigenetic modifications do occur in brain cells as cognitive skills like learning and memory develop, and that repeated activation of brain circuits dedicated to learning and memory through interaction with the environment, such as reciprocal “ serve and return ” interaction with adults, facilitates these positive epigenetic modifications. We also know that sound maternal and fetal nutrition , combined with positive social-emotional support of children through their family and community environments, will reduce the likelihood of negative epigenetic modifications that increase the risk of later physical and mental health impairments.

The epigenome can be affected by positive experiences, such as supportive relationships and opportunities for learning, or negative influences, such as environmental toxins or stressful life circumstances, which leave a unique epigenetic “signature” on the genes. These signatures can be temporary or permanent and both types affect how easily the genes are switched on or off. Recent research demonstrates that there may be ways to reverse certain negative changes and restore healthy functioning, but that takes a lot more effort, may not be successful at changing all aspects of the signatures, and is costly. Thus, the very best strategy is to support responsive relationships and reduce stress to build strong brains from the beginning, helping children grow up to be healthy, productive members of society.

For more information: Early Experiences Can Alter Gene Expression and Affect Long-Term Development: Working Paper No. 10 .

Full Text of the Graphic

“Epigenetics” is an emerging area of scientific research that shows how environmental influences—children’s experiences—actually affect the expression of their genes.

This means the old idea that genes are “set in stone” has been disproven. Nature vs. Nurture is no longer a debate. It’s nearly always both!

During development, the DNA that makes up our genes accumulates chemical marks that determine how much or little of the genes is expressed. This collection of chemical marks is known as the “epigenome.” The different experiences children have rearrange those chemical marks. This explains why genetically identical twins can exhibit different behaviors, skills, health, and achievement.

Epigenetics explains how early experiences can have lifelong impacts.

The genes children inherit from their biological parents provide information that guides their development. For example, how tall they could eventually become or the kind of temperament they could have.

When experiences during development rearrange the epigenetic marks that govern gene expression, they can change whether and how genes release the information they carry.

Thus, the epigenome can be affected by positive experiences, such as supportive relationships and opportunities for learning, or negative influences, such as environmental toxins or stressful life circumstances, which leave a unique epigenetic “signature” on the genes. These signatures can be temporary or permanent and both types affect how easily the genes are switched on or off. Recent research demonstrates that there may be ways to reverse certain negative changes and restore healthy functioning. But the very best strategy is to support responsive relationships and reduce stress to build strong brains from the beginning.

Young brains are particularly sensitive to epigenetic changes.

Experiences very early in life, when the brain is developing most rapidly, cause epigenetic adaptations that influence whether, when, and how genes release their instructions for building future capacity for health, skills, and resilience. That’s why it’s crucial to provide supportive and nurturing experiences for young children in the earliest years.

Services such as high-quality health care for all pregnant women, infants, and toddlers, as well as support for new parents and caregivers can—quite literally— affect the chemistry around children’s genes. Supportive relationships and rich learning experiences generate positive epigenetic signatures that activate genetic potential.

Study explores role of epigenetics, environment in differing Alzheimer's risk between Black and white communities

A study from North Carolina State University has found that environmentally caused alterations to specific areas of the genome -- known as imprint control regions -- during early development may contribute to the risk of developing Alzheimer's disease, and that Black people may be more affected than white people. The work adds to our understanding of the ways in which environmental factors can contribute to genetic alterations and disease susceptibility.

"In terms of genetics and disease, I always think of Dr. Kenneth Olden's analogy: genetics loads the gun and the environment pulls the trigger," says Cathrine Hoyo, professor of biological sciences at NC State and co-corresponding author of the research.

"In fact, the Institute of Medicine has estimated that epigenetic response to the environment -how our genes respond to the environment -- contributes between 70% to 90% of chronic disease risk. And we know that in the case of Alzheimer's disease, only about 5% of cases are familial, or inherited.

"We also know that the risk of developing non-familial, or sporadic, Alzheimer's differs according to race -- Black people have twice the incidence of white people," Hoyo continues. "So we wanted to see if we could identify stable epigenetic features -- parts of the epigenome that are unlikely to change once established -- that distinguished Alzheimer's brains from those without the disease."

Specifically, the research team used the imprintome -- the imprint control regions (ICRs) in the human genome that regulate the expression of imprinted genes -- to identify stable epigenetic features that distinguished people with Alzheimer's disease from those without.

Imprinted genes differ from other genes because only one parental copy of an imprinted gene is active. The other copy is methylated, or silenced, early in development. Additionally with these genes, the methylation marks that control their expression are susceptible to environmental influences.

"With imprinted genes, there isn't a backup copy in the event of mutation," says Randy Jirtle, professor of epigenetics at NC State and co-corresponding author of the research. "ICRs control the expression of these genes -- in other words, they tell imprinted genes where, when and how to work through DNA methylation. And these methylation marks in ICRs don't normally change unless altered early in development, either at conception or shortly thereafter."

For the study, the team had brain tissue samples from 17 donors -- eight normal brains and nine with Alzheimer's. Each group was divided between non-Hispanic white and non-Hispanic Black donors (the Alzheimer's group had five samples from Black donors and four from white donors).

The team sequenced the entire genome for each sample, then looked for ICRs in the Alzheimer's brains that were either over- or under-methylated compared to the healthy brains.

They found 120 differently methylated ICRs in the Alzheimer's brains. Forty were found in the combined Black and white populations; however, 81 ICRs were found only in the Black population, and 27 were found only in the white population.

The differently methylated ICRs common to both populations are associated with (MEST/MESTIT1), a paternally expressed imprinted gene, and NLRP1, a predicted imprinted gene involved in brain inflammation.

"The importance of finding the common ICRs is that it could help us develop universal tests for potential disease markers," says Hoyo. "But it was very puzzling to discover that the Black population had almost three times as many affected ICRs as the white population.

"When you see that level of difference, and you know that the changes you're finding are likely caused early by environmental interactions, one possible explanation is that there are unique or different stressors in that population, and those epigenetic effects are being passed along."

The researchers hope the work could lead to testing and targeted early interventions to prevent Alzheimer's disease.

"We know that targeted prevention over long periods can alter risk," Hoyo says. "So if you can alert people early on about their risk and apply targeted interventions, you could prevent disease onset."

"Epigenetics is the science of hope," Jirtle says. "You can't necessarily reverse genetic mutations, but when you know disease risks result from changes in the epigenome you can potentially negate them."

The work appears in Clinical Epigenetics and was supported by the National Institutes of Health under grants R01HD098857, R01MD017696, R01MD011746, P30ES025128, and R01ES032462. Brain tissue samples were provided by Duke University School of Medicine. Former NC State Ph.D. student Sebnam Cevik is first author. Other NC State contributors were David Skaar, associate research professor of biology; Antonio Planchart, associate professor of biology; and Ph.D. student Dereje Jima. Dr. Andy Liu, Dr. Truls Østbye and Dr. Heather E. Whitson of Duke University School of Medicine also contributed to the work.

Alzheimer's Research
Healthy Aging
Parkinson's Research
Alzheimer's
Racial Issues
Disorders and Syndromes
Alzheimer's disease
Human skin color
Yellow fever
Dementia with Lewy bodies
Illusion of control
Vaccination

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Materials provided by North Carolina State University . Original written by Tracey Peake. Note: Content may be edited for style and length.

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Sebnem E. Cevik, David A. Skaar, Dereje D. Jima, Andy J. Liu, Truls Østbye, Heather E. Whitson, Randy L. Jirtle, Cathrine Hoyo, Antonio Planchart. DNA methylation of imprint control regions associated with Alzheimer’s disease in non-Hispanic Blacks and non-Hispanic Whites . Clinical Epigenetics , 2024; 16 (1) DOI: 10.1186/s13148-024-01672-4

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Study Explores Role of Epigenetics, Environment in Differing Alzheimer’s Risk Between Black and White Communities

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A study from North Carolina State University has found that environmentally caused alterations to specific areas of the genome – known as imprint control regions – during early development may contribute to the risk of developing Alzheimer’s disease, and that Black people may be more affected than white people. The work adds to our understanding of the ways in which environmental factors can contribute to genetic alterations and disease susceptibility.

“In terms of genetics and disease, I always think of Dr. Kenneth Olden’s analogy: genetics loads the gun and the environment pulls the trigger,” says Cathrine Hoyo, professor of biological sciences at NC State and co-corresponding author of the research.

“In fact, the Institute of Medicine has estimated that epigenetic response to the environment –how our genes respond to the environment – contributes between 70% to 90% of chronic disease risk. And we know that in the case of Alzheimer’s disease, only about 5% of cases are familial, or inherited.

“We also know that the risk of developing non-familial, or sporadic, Alzheimer’s differs according to race – Black people have twice the incidence of white people,” Hoyo continues. “So we wanted to see if we could identify stable epigenetic features – parts of the epigenome that are unlikely to change once established – that distinguished Alzheimer’s brains from those without the disease.”

Specifically, the research team used the imprintome – the imprint control regions (ICRs) in the human genome that regulate the expression of imprinted genes – to identify stable epigenetic features that distinguished people with Alzheimer’s disease from those without.

“With imprinted genes, there isn’t a backup copy in the event of mutation,” says Randy Jirtle, professor of epigenetics at NC State and co-corresponding author of the research. “ICRs control the expression of these genes – in other words, they tell imprinted genes where, when and how to work through DNA methylation. And these methylation marks in ICRs don’t normally change unless altered early in development, either at conception or shortly thereafter.”

For the study, the team had brain tissue samples from 17 donors – eight normal brains and nine with Alzheimer’s. Each group was divided between non-Hispanic white and non-Hispanic Black donors (the Alzheimer’s group had five samples from Black donors and four from white donors).

The team sequenced the entire genome for each sample, then looked for ICRs in the Alzheimer’s brains that were either over- or under-methylated compared to the healthy brains.

They found 120 differently methylated ICRs in the Alzheimer’s brains. Forty were found in the combined Black and white populations; however, 81 ICRs were found only in the Black population, and 27 were found only in the white population.

“The importance of finding the common ICRs is that it could help us develop universal tests for potential disease markers,” says Hoyo. “But it was very puzzling to discover that the Black population had almost three times as many affected ICRs as the white population.

“When you see that level of difference, and you know that the changes you’re finding are likely caused early by environmental interactions, one possible explanation is that there are unique or different stressors in that population, and those epigenetic effects are being passed along.”

The researchers hope the work could lead to testing and targeted early interventions to prevent Alzheimer’s disease.

“We know that targeted prevention over long periods can alter risk,” Hoyo says. “So if you can alert people early on about their risk and apply targeted interventions, you could prevent disease onset.”

“Epigenetics is the science of hope,” Jirtle says. “You can’t necessarily reverse genetic mutations, but when you know disease risks result from changes in the epigenome you can potentially negate them.”

Note to editors: An abstract follows.

“DNA methylation of imprint control regions associated with Alzheimer’s disease in non-Hispanic Blacks and non-Hispanic Whites”

DOI: 10.1186/s13148-024-01672-4

Authors: Sebnem E. Cevik, David A. Skaar, Dereje D. Jima, Randy L. Jirtle, Cathrine Hoyo, Antonio Planchart, North Carolina State University; Andy J. Liu, Truls Østbye, Heather E. Whitson, Duke University Published: April 25, 2024 in Clinical Epigenetics

Abstract: Alzheimer’s disease (AD) prevalence is twice as high in non-Hispanic Blacks (NHBs) as in non-Hispanic Whites (NHWs). The objective of this study was to determine whether aberrant methylation at imprint control regions (ICRs) is associated with AD. Differentially methylated regions (DMRs) were bioinformatically identified from whole-genome bisulfite sequenced DNA derived from brain tissue of 9 AD (5 NHBs and 4 NHWs) and 8 controls (4 NHBs and 4 NHWs). We identified DMRs located within 120 regions defined as candidate ICRs in the human imprintome (https://genome.ucsc.edu/s/imprintome/hg38.AD.Brain_track). Eighty-one ICRs were differentially methylated in NHB-AD, and 27 ICRs were differentially methylated in NHW-AD, with two regions common to both populations that are proximal to the inflammasome gene, NLRP1, and a known imprinted gene, MEST/MESTIT1. These findings indicate that early developmental alterations in DNA methylation of regions regulating genomic imprinting may contribute to AD risk and that this epigenetic risk differs between NHBs and NHWs.

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Review article, epigenetics across the human lifespan.

Epigenetics Laboratory, Department of Anatomy, Howard University, Washington, DC, USA

Epigenetics has the potential to explain various biological phenomena that have heretofore defied complete explication. This review describes the various types of endogenous human developmental milestones such as birth, puberty, and menopause, as well as the diverse exogenous environmental factors that influence human health, in a chronological epigenetic context. We describe the entire course of human life from periconception to death and chronologically note all of the potential internal timepoints and external factors that influence the human epigenome. Ultimately, the environment presents these various factors to the individual that influence the epigenome, and the unique epigenetic and genetic profile of each individual also modulates the specific response to these factors. During the course of human life, we are exposed to an environment that abounds with a potent and dynamic milieu capable of triggering chemical changes that activate or silence genes. There is constant interaction between the external and internal environments that is required for normal development and health maintenance as well as for influencing disease load and resistance. For example, exposure to pharmaceutical and toxic chemicals, diet, stress, exercise, and other environmental factors are capable of eliciting positive or negative epigenetic modifications with lasting effects on development, metabolism and health. These can impact the body so profoundly as to permanently alter the epigenetic profile of an individual. We also present a comprehensive new hypothesis of how these diverse environmental factors cause both direct and indirect epigenetic changes and how this knowledge can ultimately be used to improve personalized medicine.

Introduction

The literal meaning of the term epigenetic is “on top of or in addition to genetics.” The series of chemical tags that modify DNA and its associated structures constitute the epigenome, and include any genetic expression modifier independent of the DNA sequence of a gene. The genome defines the complete set of genetic information contained in the DNA, residing within the cells of each organism. The epigenome, on the other hand, comprises the complex modifications associated with genomic DNA, imparting a unique cellular and developmental identity.

The epigenome integrates the information encoded in the genome with all the molecular and chemical cues of cellular, extracellular, and environmental origin. Along with the genome, the epigenome instructs the unique gene expression program of each cell type to define its functional identity during development or disease ( Rivera and Ren, 2013 ).

The epigenome also, in some sense, represents the ability of an organism to adapt and evolve through expression of a set of characteristics or phenotypes developed in response to environmental stimuli.

Thus, in contrast to the consistency of the genome, the epigenome is characterized by a dynamic and flexible response to intra- and extra-cellular stimuli, through cell-cell contact, by neighboring cells, by physiology, or entirely by the environment that the organism is exposed to Figure 1 . Cytokines, growth factors, alterations in hormonal levels as well as release of stress-response and neurotropic factors are some examples of molecules that are modulated by the environment and which come under the category of epigenome modifiers. Ultimately, the environment presents these various factors to the individual that influence the epigenome, and the unique epigenetic and genetic profile of each individual also modulates the specific response to these factors (Figure 1 ).

Figure 1. A compilation of epigenetic influences on humans . The figure represents a compilation of the various epigenetic influences on humans by different sources present in the environment. While some of these might be beneficial for health and behavior, others might be harmful and interfere with the body and mind creating an imbalance, which might manifest as a disease or psychological disorder. Some of the beneficial influences listed are exercise, microbiome (beneficial intestinal bacteria), and alternative medicine whereas harmful influences include exposure to toxic chemicals and drugs of abuse. Factors such as diet, seasonal changes, financial status, psychological state, social interactions, therapeutic drugs, and disease exposure might have beneficial or harmful effects depending on the specific nature of the influence. The environment thus complements and shapes human health. With the help of extended research in the field, we might be able to steer these influences in a positive way.

Enzymatic activity in response to the environment promotes addition or removal of epigenetic tags on DNA and/or chromatin, sparking a cavalcade of changes that affect cellular memory transiently, permanently or with a heritable alteration. Some of the molecular mechanisms involved in this process are explained in more detail below.

Mechanisms Underlying Epigenetics

As explained, every cell in the organism carries an identical genome, however, despite the stability of these instructions, the terminal phenotype within an organism is not fixed and deviation is caused by gene expression changes in response to environmental cues. DNA methylation, histone modification and RNA-associated silencing are the major ways these changes are controlled, which are described in more detail below.

DNA Methylation

The methylome is the genomic distribution of methylated DNA sequence present in a cell and is capable of undergoing modification with respect to the environment or the developmental stage. DNA methylation involves the covalent addition of a methyl group at position 5 of the pyrimidine ring of cytosine that is represented as 5-methyl C or C Me . Transcription of most protein coding genes in mammals is initiated at promoters rich in CG sequences, where cytosine is positioned next to a guanine nucleotide linked by a phosphate called a CpG site. Such short stretches of CpG-dense DNA are known as CpG islands. In the human genome 60–80% of 28 million CpG dinucleotides are methylated ( Lister et al., 2009 ; Ziller et al., 2013 ). Chromatin structure adjacent to CpG island promoters facilitates transcription, while methylated CpG islands impart a tight compaction to chromatin that prevents onset of transcription and therefore, gene expression.

In CpG islands active C's are normally unmethylated and when an unmethylated cytosine spontaneously deaminates to uridine, it is converted back to cytosine by DNA repair mechanisms, thus preserving CpG sequences through evolution. The presence of 5-methyl C in a CpG island denotes an inactive promoter owing to the condensation of chromatin triggered by DNA methylation.

CpG sites are methylated by one of three enzymes called DNA methyltransferases (DNMTs). A variety of DNMTs are responsible for DNA methylation patterns established during embryogenesis. One type of DNA methyltransferase, DNMT1, is responsible for maintaining normal methylation patterns by copying them exactly between cell generations during replication. DNMT2 is associated with embryonic stem cells and potential RNA methylation. DNMT3a and DNMT3b are involved in de novo DNA methylation at CpG sites ( Clouaire and Stancheva, 2008 ; Singh and Li, 2012 ).

Histone Modification

Histones are the core protein components of chromatin complexes, and they provide the structural backbone around which DNA wraps at regular intervals generating chromatin. The nucleosome represents the first level of chromatin organization and is composed of two of each of histones H2A, H2B, H3, and H4, assembled in an octameric core with DNA tightly wrapped around the octamer ( Luger et al., 1997 ). Histones regulate DNA packaging with immense influence on the degree of chromatin compaction, influencing transcriptional activity as well as transcriptional silencing.

Histone modifications are post-translational changes on the histone tails, that are flexible stretches of N or C terminal residues extending from the globular histone octamer. Modifications of histones include acetylation of lysine residues, methylation of lysine and arginine residues, phosphorylation of serine and threonine residues, and ubiquitination of lysine residues present on histone tails, as well as sumoylation and ADP ribosylation. All of these changes influence DNA transcription. Addition or removal of methyl groups on DNA (see above) and histones and acetyl groups on histones are the prime mechanisms of changing the epigenetic landscape ( Cedar and Bergman, 2009 ).

Histone acetylation is carried out by enzymes called histone acetyltransferases (HATs), that are responsible for adding acetyl groups to lysine residues on histone tails while histone deacetylases (HDACs) are those that remove acetyl groups from acetylated lysines. Generally, presence of acetylated lysine on histone tails leads to a relaxed chromatin state that promotes transcriptional activation of selected genes; in contrast, deacetylation of lysine residues leads to chromatin compaction and transcriptional inactivation.

RNA Silencing

RNA-associated silencing is a type of post-transcriptional gene modification during which the expression of one or more genes is downregulated or suppressed by small non-coding stretches of RNA, sometimes called microRNAs (miRNA) and small interfering RNAs (siRNA). Although microRNAs only represent 1% of the genome they have been estimated to target 30% of genes ( Lewis et al., 2005 ). These RNAs can act as switches and modulators, exerting extensive influence within the cell and beyond. These RNAs fine-tune the gene expression as they act as specific modulators based on cell-type specificity of the organism during development as well as pathological conditions ( Giraldez et al., 2005 ; Girardot et al., 2012 ; Baer et al., 2013 ). Also, miRNAs have been known to play a role in tumor suppression, apoptosis, cellular proliferation and cell movement which suggests that they can be manipulated in treating epigenetic diseases like cancer ( Kala et al., 2013 ).

Putative mechanisms of RNA silencing include the ability of non-coding RNA to negatively regulate expression of target genes at the posttranscriptional level by binding to 3′-untranslated regions of target mRNAs resulting in their degradation ( Singh et al., 2008 ).

All genes in every cell type are activated or silenced by an underlying interplay between these described epigenetic mechanisms. And as explained in the Introduction, exogenous epigenetic forces modify the endogenous inherited epigenetic pattern.

Endogenous and Exogenous Epigenetic Regulation of Genes

In order to illustrate the endogenous epigenetic regulation of a gene, we will use the example of OCT4. OCT4 is the master pluripotency gene, which is regulated through different stages of human development, and its activation is necessary for maintaining pluripotency, whereas it must be silenced in order for a cell to differentiate ( Kellner and Kikyo, 2010 ) (Figure 2 ). OCT4 is thus active in embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) as well as in cancer cells, but is silenced in differentiated cell types. The three types of epigenetic modifications explained above i.e., DNA methylation, histone modification and RNA silencing are responsible for such regulation of OCT4 gene expression. This has been illustrated in detail along with the various epigenetic tags involved in its regulation in Figure 2 .

Figure 2. Epigenetic regulation of OCT4 in stem cells, cancer cells and somatic cells . The figure represents the various epigenetic mechanisms involved in regulating the gene expression of OCT4. (A) This section represents the structure of the OCT4 gene. The green bar represents the coding region. The beige bar represents the upstream region containing regulatory sequences. The four pink bars represent conserved regions; CR1 (−129 to −1), CR2 (−1510 to −1315), CR3 (−1956 to −1852), CR4 (−2557 to −2425) (data for human OCT4 gene). The green triangles represent the sites for binding of activators and the red squares represent the sites for binding of the repressors and these sites lie within the enhancers and promoter. +1 denotes transcription start site (TSS). (DE, Distal Enhancer −2057 to −1955; PE, Proximal Enhancer −1152 to −901; PP, Proximal Promoter −240 to +1) (This data is for the OCT4 gene from mouse ESCs since information for human OCT4 was insufficient). (B) This section represents the regulation of OCT4 in ESCs and iPSCs. OCT4 is highly expressed in these cells. Binding of transcriptional machinery induces OCT4 expression. This can be attributed to the hypomethylated promoter, enhancer region, which promotes binding of transcriptional activators and co-activators like Pcaf, LRH−1, SF−1, and Brg1 sub-unit of the SWI-SNF nucleosome-remodeling complex, which in turn facilitates the binding of RNA polymerase II. Activating histone marks like H3K4me and H3K9Ac are found on the histones surrounding the regulatory regions of the gene and they enhance the recruitment and binding of transcription factors thus inducing gene expression. (C) This section represents the regulation of the OCT4 gene in cancer cells, where similar to embryonic-like cells, it is highly expressed. In the case of hepatocellular carcinoma, an additional layer of epigenetic regulation is seen with the activity of the OCT4-pseudogene (pg)4, a non-coding RNA that protects the OCT4 transcript from inhibition by miRNA-145. Thus, OCT4-pg4 indirectly enhances the expression of OCT4 in cancer cells by acting as a protective shell for nascent OCT4 transcripts. The activity of the Brg1 sub-unit of the SWI-SNF complex is not necessary for OCT4 expression in cancer cells. (D) This section represents the regulation of OCT4 in somatic cells, which are differentiated and have a specialized function. Here OCT4 expression is repressed because of the hypermethylated promoter region and the repressive H3K27me and H3K9me marks. This results in compaction of the regulatory regions and facilitates the recruitment of other transcriptional repressors like RAR, GCNF, COUP-TFs, further compacting the regulatory regions, and making it inaccessible to the transcriptional machinery. SNF5, a core sub-unit of the BAF complex (SWI-SNF) acts as a switch between pluripotency and differentiation and promotes differentiation by binding to regulatory regions of OCT4. In addition, the sumyolation of orphan nuclear receptor Tr2 at Lys 238 results in its release from promyelocytic (PML) nuclear bodies. (In ESCs and iPSCs Tr2 is bound to PML nuclear bodies and acts as an activator). This in turn results in an exchange of co-repressor Rip-140 for co-activator Pcaf, making Tr2 a repressor. Also, miR-290 through miR-295 enhance methylation as they inhibit Rb12, which would otherwise inhibit the activity of de novo methyl transferase Dnmt 3a/3b.

In a similar way, let us consider the effect of exogenous epigenetic forces on the expression of OCT4. Vitrification, which is a commonly used method for cryopreservation, has been documented to alter the methylation patterns of the OCT4 gene. In two such cases, vitrification resulted in decreased methylation of the OCT4 promoter causing reduced gene expression in mouse blastocysts and the same was observed for mouse oocytes that underwent vitrfication followed by in vitro maturation ( Milroy et al., 2011 ; Zhao et al., 2012 ). This explains how the external environment, in this case temperature, can lead to alteration of the epigenetic profile of one or many genes, ultimately causing differential gene expression.

How do Cellular Biochemical Changes Cause Epigenetic Changes? A Hypothetical Mechanism

The effects of an epigenetic factor can be manifested as a global change in DNA methylation affecting multiple genes, or modified expression of very specific genes. The mechanisms and cellular pathways that are involved in the creation of these global or specific epigenetic changes are currently obscure. Below we describe a working hypothesis on how these changes might occur.

We propose that an epigenetic factor can act through either a direct or an indirect mechanism (Figure 3 ). A direct effect could happen in two ways; which we term Type 1 and Type 2. Type 1 direct effect occurs when the epigenetic factor directly alters the state of epigenetic enzymes—either by binding to them and preventing them from carrying out their normal function, damaging them in some other way, or upregulating them. The altered bioavailability of epigenetic enzymes then results in aberrant recruitment of epigenetic tags to promoters and enhancers on a genome-wide scale. Such a direct effect would be effective across the entire genome, not affecting any specific gene but resulting in a randomly altered epigenome. An example of a directly acting epigenetic factor is the antihypertensive hydralazine, which inhibits DNA methylation.

Figure 3. The direct and indirect epigenetic pathway . The figure represents two different routes through which an epigenetic factor can modify the epigenome leading to altered gene expression. Epigenetic effects exerted by an external factor or intrinsic environment can lead to direct and indirect effects on the epigenome. Green represents direct effects of an epigenetic factor and red represents indirect effects of an epigenetic factor. The direct pathway can operate in two different ways; namely Type1 and Type 2. In the Type 1 direct pathway, the epigenetic factor directly exerts an effect on the epigenetic enzymes such as DNMTs, HDACs, HATs, HMTs, HDMs, etc. such that there is an altered bioavailability of these enzymes in the cell. A Type 2 direct effect is when an epigenetic factor interferes with a biochemical pathway such that there is altered availability of a metabolite required for constituting an epigenetic tag. Both cases can result in aberrant or inadequate recruitment of epigenetic tags in a random fashion to non-specific promoters, ultimately establishing an altered epigenetic profile. In the indirect pathway, the epigenetic factor indirectly exerts an effect on the epigenome by first interfering with any signaling pathways of the cell. An acute exposure to the epigenetic factor can cause altered expression of growth factors, receptors, ion channels and so on resulting in non-homeostatic cellular processes. This in turn might lead to an altered status of transcriptional machinery (bound or unbound to the promoter/enhancer) and its bioavailability in a cell. A chronic exposure to the epigenetic factor might lead to retention of such state of transcriptional machinery (bound or unbound to the promoter/enhancer) causing altered gene expression as well as aberrant recruitment of epigenetic enzymes, leading to permanent addition or removal of epigenetic tags to specific promoter/enhancers. This consequently establishes an altered epigenetic profile.

Type 2 direct effects occur when an epigenetic factor causes a change in a biochemical process that results in an altered availability of a substrate, intermediate, by-product or any other metabolite participating in the biochemical pathway, that is used to make up epigenetic tags (for example acetate). This in turn leads to altered availability of epigenetic tags, in this case acetyl groups on histones, which leads non-specific modification of the epigenome (Figure 3 ).

The second major way that factors can cause epigenetic changes is by what we term indirect mechanisms (Figures 3 , 4 ). A biphasic mechanism is postulated for indirect effects in which acute exposure to a factor influences cellular signaling pathways that leads to altered expression of growth factors, receptors and ion channels, which in turn alter transcription factor activity at gene promoters. With more chronic exposure, the transcription factors and other gene regulatory proteins, in addition to altering gene expression activity, actually recruit or repel epigenetic enzymes to/from the associated chromatin, resulting in the addition or removal of epigenetic tags (Figure 4 ). In this way cells adapt to the persistent gene expression changes by causing permanent modifications to DNA methylation and chromatin structure, leading to enduring alteration of the affected epigenetic network (Figures 3 , 4 ). An example of an indirectly acting factor is the drug isotretinoin, which has transcription factor activity.

Figure 4. The indirect epigenetic pathway . An epigenetic factor operating through an indirect pathway interferes with transcriptional machinery. Chronic exposure to an epigenetic factor can lead to the retention of an already altered state of transcriptional machinery. The transcriptional machinery (bound or unbound to the gene regulatory regions i.e., promoters/enhancers) includes a number of proteins like transcription factors, activators and co-activators, repressors and co-repressors and nucleosome or chromatin remodeling complexes. For simplicity, these proteins are Fectively termed as “Gene regulatory protein” for this figure. (A) A gene regulatory protein might affect the status of RNA Polymerase (1) By inhibiting it from binding to a transcriptional apparatus or forming one or (2) by facilitating the binding of RNA Polymerase as well as formation of a transcriptional apparatus essential for the initiation of transcription. (B) A gene regulatory protein might also affect the status of epigenetic enzymes like DNMTs, HDACs, HATs, HMTs, HDMs, etc., which are responsible for the addition or removal of epigenetic tags (methyl group on DNA or histone, acetyl group on histones) on gene regulatory regions. This can be (1) By inhibiting epigenetic enzymes from binding to the gene regulatory regions and hence prohibiting the addition or removal of epigenetic tags (2) By facilitating the binding of epigenetic enzymes to gene regulatory regions and hence allowing the addition or removal of epigenetic tags. Such retention of a gene regulatory protein due to chronic exposure to an epigenetic factor might result in a permanent change in the epigenetic profile and/or gene expression of a specific gene affected by that epigenetic factor through an indirect pathway.

Epigenetic factors known to cause such direct and indirect effects are well-documented but their exact mechanism has not been accurately elucidated. For example, nutritional interventions in adulthood like caloric restriction can induce epigenetic changes that have the potential to alleviate age-related diseases ( Bacalini et al., 2014 ). In caloric restriction food intake is intentionally reduced by 30–50% ( Zakhari, 2013 ) and has been shown to delay the aging process in mice by decreasing the levels of histone deacetylase 2 (HDAC2) which otherwise increases during the normal aging process ( Chouliaras et al., 2013 ). Thus, this is an example of direct effect by an epigenetic influence (caloric restriction).

Another example is curcumin, a polyphenol found in turmeric, which can be regarded as a dietary epigenetic factor. It is an inhibitor of the Histone acetlytransferase p300/CBP (co-activator) and GATA4 (a zinc finger transcription factor), which leads to decrease in nuclear acetylation induced during myocardial cell hypertrophy ( Morimoto et al., 2008 ). The possible mechanisms through which curcumin exerts such an effect might be through allosteric regulation of p300 or through interfering with nuclear signaling pathways like transcriptional activation by NF-κB ( Morimoto et al., 2008 ). Hence the epigenetic effect of curcumin is an example of a combined direct and indirect effect.

Epigenetics Across the Human Lifespan

In this main section of the paper, we describe the major epigenetic milestones in the human lifespan, integrated chronologically with the various environmental factors that affect the human epigenome and the interaction with these milestones (Figure 6 ).

In differentiated cells, signals fine-tune cell functions through changes in gene expression across the lifespan. A flexible epigenome allows us to adjust to changes in the world around us, and to “learn” from our experiences. In many ways, epigenetic expression can be thought of as the “software” of the genome and directs embryogenesis and development, as well as influences the development of an individual's body and brain after birth. Unique sets of genes are induced or silenced epigenetically during different stages of life and these are responsible for the development and maturation of the individual through orchestrated events in combination with input from the environment. Any kind of epigenetic factors influencing genes or gene expression networks during life stages can result in an imbalance in the regulation process, and might have a life-long effect on the individual. While such flexibility gives rise to beneficial adaptability to environmental conditions, it likewise allows weaknesses to integrate and exert negative and diseased outcomes on both individual and evolutionary scales.

We have used data from human studies in most cases in this review, but in some cases where such data is sparse or unavailable, we have supported our explanations with data from studies on rodent and/or other animal models.

From the Periconceptional Environment to Birth

For most genes, total reprogramming is necessary very soon after conception in order to start with an epigenetic “clean slate,” which then allows all of the specialized cells derived from the egg and sperm to develop with stable cell-specific gene expression profiles and remain properly differentiated. This happens in the fertilized egg: global DNA demethylation is followed by remethylation to reprogram the maternal and paternal genomes for efficient gene expression regulation. As a fertilized egg develops into a human baby, signals received cause steady changes in gene expression patterns. Epigenetic tags physically record the cell's experiences on the DNA, and stabilize gene expression. Each signal activates some genes, and inactivates others, as the cell develops toward its final fate. Early in development, most signals come from within cells or from neighboring cells. Different experiences cause the epigenetic profiles of each cell type to grow increasingly different over time. Eventually, hundreds of cell types form, each with a distinct identity and specialized function. Specifc genes are turned on and off at certain time intervals, and any disruption of this finely-tuned DNA methylation regulation may persistently alter gene expression. The fetal epigenome is most susceptible during this developmental period to epigenetic modifiers in the maternal environment. An error during such a crucial time might lead to an abnormal phenotypic outcome in the offspring.

Assisted reproductive technologies (ARTs) like IntraCytoplasmic Sperm Injection (ICSI) and in vitro feritlization (IVF), which are used in case of male or female sub-fertility, cause epigenetic changes in offspring such that there is differential allelic expression in the early embryo ( Kohda and Ishino, 2013 ). While comparing the two ARTs, ICSI, and IVF, both result in epigenetic errors owing to aberrant DNA methylation, but neither one has an increased effect as compared to the other ( Santos et al., 2010 ). It has been shown that the use of ICSI results in hypermethylation of the Small Nuclear RiboNucleoprotein Polypeptide N gene (SNRNP) indicating likely mRNA splicing errors, which might result in such offspring ( Whitelaw et al., 2014 ) (Figure 6 ).

Studies have also shown that ART can increase the risk of adverse pregnancy outcomes and imprinting errors resulting in incorrectly silenced genes ( Bowdin et al., 2007 ; Reddy et al., 2007 ). As already mentioned in Section Endogenous and Exogenous Epigenetic Regulation of Genes, vitrification, which is also used in cryopreservation of embryos, leads to decreased methylation of OCT4 as well as other genes ( Milroy et al., 2011 ; Zhao et al., 2012 ) further suggesting that ART is capable of altering the epigenetic profile, which might cause serious complications in future progeny.

Maternal influences

Maternal health can predict childhood development, health outcome and disease consequences. More specifically, fetal programming describes how the in utero environment impacts molecular development in the fetus via epigenetic remodeling ( Barker and Clark, 1997 ; Schuz, 2010 ). Specific examples include the observation that reprogramming of the developing zygote involves conversion of 5-methylcytosine to 5-hydroxymethylcytosine ( Wossidlo et al., 2011 ).

Maternal diet. A mother's diet and stress influence the fetus in utero and can cause epigenetic changes as well. A study based on maternal folic acid supplementation showed that the offspring of mice fed with folic acid had a distinct global DNA methylation pattern compared to that of the offspring of mice which received a low folic acid dosage, involving genes associated with autism spectrum disorder (ASD) pathogenesis ( Barua et al., 2014 ). The data supports the studies on the complexity of epigenetic regulation of genes GAD1 and RELN in ASD ( Zhubi et al., 2014 ).

Also, experiments wherein maternal diet modification was the only variable were able to improve health outcome and increase longevity in offspring without changing DNA sequence. For example pregnant agouti mice, which are a strain predisposed to severe obesity, when fed diets supplemented with genistein, give birth to totally normal pups ( Dolinoy et al., 2006 ).

Epigenetic effects of periconceptional diet on the DNA methylation status of rural Gambians shows that altered nutritional status of mothers during seasonal (weather) changes results in epigenetic variation in the three germ layers of offspring born during different seasons, including differential birth weight, and these changes persist through adulthood ( Waterland and Jirtle, 2003 ).

Maternal smoking. Other maternal effects include cigarette smoking, which during pregnancy can cause altered DNA methylation and micro RNA expression ( Knopik et al., 2012 ).

Maternal mental health and social environment. Maternal psychological health also exerts a powerful influence over the epigenetic outcome in offspring. In rats, prenatal stress during late gestation has been shown to modify epigenetic signatures that are linked to neurological disease during the critical period of fetal brain development ( Zucchi et al., 2013 ). Also, domestic violence triggers stress in pregnant women that results in epigenetic changes in the DNA of the cortisol receptor in offspring observed during adolescence ( Radtke et al., 2011 ).

Paternal influences

Environmentally induced epigenetic variation is also driven by paternal factors, and they are as important as their maternal counterparts in influencing epigenetic outcome in offspring ( Carone et al., 2010 ; Hughes, 2014 ). During embryogenesis and fetal growth the insulin–like growth factor 2 (IGF2) gene is regulated by DNA methylation. Imprint marks are erased in primordial germ cells early in the process and new methylation patterns are created. Only paternal IGF2 is transcribed in normal tissues ( Dechiara et al., 1991 ). New evidence indicates that paternal obesity is associated with a decrease in DNA methylation at IGF2 ( Soubry et al., 2013 ).

Also, DNA methylation in sperm can be influenced by paternal alcohol consumption, and paternal exposure to toxic chemicals such as vinclozolin and chromium chloride likewise alters the germ line epigenome ( Cheng et al., 2004 ; Anway et al., 2005 ; Ouko et al., 2009 ; Stouder and Paoloni-Giacobino, 2010 ). Also, folate deficiency in male mice affects sperm function involving differential DNA methylation compared to control and the male offspring of such folate deficient mice show an altered gene expression compared to offspring born to control mice ( Lambrot et al., 2013 ).

Developmental/in utero influences

Imprinted genes have trans-generationally stable DNA methylation patterns oblivious to the normal resetting that occurs early in normal development. These imprinted epigenetic marks are passed from parent to progeny on gametes, evading the normal epigenetic purging process that occurs during gamete formation, as described above. If a particular epigenetic profile is to pass to the next generation, the epigenetic tags associated with it must avoid erasure during reprogramming. Typically, a small minority of genes possesses epigenetic tags that survive the reprogramming process and pass unchanged from one generation to the next.

One such example is the neurological epigenetic disease called Angelman syndrome, that results from epigenetic silencing of the paternal UBE3 allele combined with a mutation or deletion in the maternal UBE3 allele, resulting in loss of E3 ubiquitin ligase, leading to multiple neuronal defects like epilepsy, ataxia, etc. ( Rudenko and Tsai, 2014 ). Such epigenetic alterations based on comparison with a normal epigenetic profile can be considered useful biological markers for investigating neuropsychiatric symptoms of mental disorders with the help of new technologies like MeD-Chip sequencing ( Fass et al., 2014 ).

Imprinted genes possess molecular memory of their germ line, associated with a variety of allelic DNA methylation patterns affecting genotype. But imprinted genes are still subject to epigenetic reprogramming following environmental exposures. Exposure to certain dioxin compounds induces DNA methylation in imprinted genes ( Surani, 2001 ). Similarly, certain mammals respond to a hormonally triggered type of diabetes during pregnancy, known as gestational diabetes. Maternal gestational diabetes causes the developing fetus to be exposed to high levels of glucose. The high glucose in turn triggers epigenetic changes in the progeny DNA, often resulting in gestational diabetes in the next generation. Studies in rats with the proximal promoter region of Pdx1 , a duodenal and pancreatic specific homeobox transcription factor reveal that onset of diabetes was associated with permanent silencing of the locus ( Park et al., 2008 ).

In females, random X-chromosome inactivation is initiated during gastrulation in the epiblast through the X-inactive specific transcript (Xist) gene, which encodes a long non-coding RNA that silences the X-chromosome transcribing it ( Reik, 2007 ).

Thus, as a fertilized egg develops into an embryo to fetus to a baby, numerous signals over the course of development cause incremental changes in expression of the genetic profile (Figure 6 ). Even in differentiated cells, signals will fine-tune cellular function by altering gene expression. Ultimately the flexibility inherent in the epigenome allows adjustments in response to the changing environment and the ability for future generations to successfully evolve and learn from earlier experience ( Barlow and Bartolomei, 2014 ).

Perinatal Effects

Epigenetic influences continue to shape an individual after birth. Even at birth, the type of delivery seems to have an effect on the offspring being born. For example, offspring born from ceasarian section have shown to have global hypermethylation in leucocytes as compared to those born vaginally ( Schlinzig et al., 2009 ).

Infancy and childhood

After birth and as life continues, a wider variety of environmental factors begin to play a role. As in early development, signals from within the body continue to be important for many processes, including physical growth and learning, but gradually more and more external environmental and social influences begin to take effect. For example, groundbreaking studies on the ability of behavior to modify the epigenome were conducted and demonstrated the important interplay between social and physical processes ( Weaver et al., 2004 ). Early life positive and negative experiences like maternal care, stress adaptation, and early life adversities contribute to a biological memory, and epigenetic modifications of DNA are responsible for imprinting such influences in to the neuronal circuits of the developing brain which can have life-long impacts ( Hoffmann and Spengler, 2014 ).

Maternal care and interaction

During infancy and childhood maternal care and social environment shape a child's psychology ( Fagiolini et al., 2009 ). Maternal bonding has a profound effect on the physical and psychological welfare of children. Epigenetic mechanisms interact with and impact the hypothalamic-pituitary-adrenal axis of the stress response in the brain. For example, in mice, absence of maternal grooming epigenetically modifies DNA methylation, which alters glucocorticoid receptor expression. This leads to increased cortisol production by the adrenal glands and increases the stress response in pups ( Plotsky and Meaney, 1993 ).

Also, murine maternal care like licking and grooming (LG) and arched back nursing (ABN) resulted in increased levels of hippocampal N-methyl D-aspartate receptor (NMDAR) and brain-derived neurotrophic factor (BDNF) in infant rats leading to increased neural synaptogenesis and enhanced spatial learning in adulthood ( Meaney, 2001 ). Also pups experiencing frequent licking and grooming by their mother exhibit decrease in stress and anxiety through adulthood as a result of epigenetic changes at cortisol receptors ( Weaver et al., 2004 ). Maternal care in rats has demonstrated decreased methylation of the offspring Grm1 gene encoding metabotropic glutamate receptor (mGluR1) denoting epigenetic control of genes involved in glutamatergic synaptic signaling thereby influencing hippocampal function and cognitive performance ( Bagot et al., 2012 ).

Licking by mother rats of their pups activates the NRC31 gene in the hippocampus of the brain and as a result protects the pups against stress ( Oberlander et al., 2008 ; Bromer et al., 2013 ) (Figure 4 ). This epigenetically induced modification of DNA observed in rats is reversible, with remethylation of glucocorticoid receptors occurring in response to methionine injection ( Waris and Ahsan, 2006 ). Presumably, therefore, it may be possible to prevent or reverse the onset of similar damaging epigenetic modifications in human children through behavioral therapy such as hugging, cuddling and other nurturing and stress-alleviating activities.

On the other hand, increased levels of corticotropin- release factor (CRF) in pups as a result of maternal separation was shown to be associated with serious mood disorders in adulthood ( Meaney, 2001 ) There is similar evidence that suicide victims with a history of domestic violence and childhood abuse showed increased DNA methylation of the glucocorticoid receptor (NR3C1) gene leading to increased HPA (hypothalmis-pitutary-adrenal axis) activity resulting in elevated stress levels, also suggesting that suicide has a developmental origin ( McGowan et al., 2009 ) (Figure 6 ).

Poverty and neglect have direct negative impacts upon future development ( McGowan et al., 2009 ). The quality of family life including maternal care continues to influence the physiology and psychology of the child such that persistent neglect, emotional or sexual abuse hamper growth and intellectual development and increase risk of disorders like obesity during adulthood ( Meaney, 2001 ).

More positively, epigenetic analysis of the serotonin transporter gene can be used for screening soldiers and identifying those at a greater risk for Post-traumatic stress disorder (PTSD) based on childhood trauma and thus specific epigenetic signatures can help in improvement of training regimens of such soldiers at a higher risk in order to avoid PSTD ( Miller, 2011 ).

Adolescence

The transition from childhood to adolescence is accompanied by temperamental and behavioral changes including emergence of sexual behavior which is driven by underlying hormonal changes that can also be influenced by environmental factors ( Laviola et al., 2003 ). Puberty is a primary event of adolescence and is itself a major development event of human life. The HPG (hypothalamic-pitutary-gonadal) axis, which is dormant during childhood, is now activated ( Seminara et al., 2003 ) which results in a sustained increase in gonadotropin-releasing hormone (GnRH) ( Ojeda et al., 2010 ).

Puberty involves the maturation of certain regions of the pre-frontal cortex in the brain, and it has been suggested that environmental influences like stress can trigger neuropsychiatric diseases via epigenetic mechanisms during such vulnerable plastic development ( Morrison et al., 2014 ). Puberty in females involves maturation of specific brain regions along with the increased expression of genes like KISS-1 (kisspeptin), NKB (neurokinnin B), GPR54, TAC3 along with decreased expression of two genes Eed and Cbx7 (polycomb group proteins) leading to the beginning of estrous cycle ( Lomniczi et al., 2013 ; Morrison et al., 2014 ).

Puberty in females also leads to menarche i.e., the beginning of the menstrual cycle in females. The menstrual cycle is an orchestrated event that operates through a 28 day period during which the endometrium undergoes cyclic morphological transformations of growth, differentiation and regression ( Munro et al., 2010 ). We have illustrated the epigenetic fluctuations (global histone acetylation) governing the gene expression in the endometrium through this cycle (Figure 5 ).

Figure 5. Chronology of epigenetic regulation during the circadian rhythm and menstrual cycle . The regulation of biological cycles like the Circadian rhythm and Menstrual cycle in females has been shown to work through epigenetic regulatory mechanisms. (The figure is relative and not accurate to scale). (A) The gene Bmal1 is the master regulator of the circadian rhythm. The graph represents the relative density of the two active histone marks H3K3me and H3K4me on Bmal1 through a 26-hour period. ZT is Zeitgeber Time where ZT0 corresponds to light on and ZT12 to light off. The peaks represent the maxima of the two-histone marks with respect to ZT, similarly, the dips represent the minima. This shows differential expression of the gene with respect to time, which has an epigenetic regulatory basis. (B) The graph represents the global acetylation profile from endometrial tissue through the 28-day menstrual cycle. The peaks represent the maxima and the dips represent the minima of the histone marks with respect to time. Global changes in the histone acetylation profile show that these marks contribute to the induction of different genes during different stages of the cycle. Hence they are responsible for the variable morphology of the endometrium through the 28-day period. These epigenetic changes are thus the basis for changes in the endometrial morphology like regeneration (1–7 days), proliferation (7–14 days), ovulation (13–17 days), differentiation (15–22 days), degradation (22–28 days) during the proliferative phase and secretory phase.

Early life experiences modify the neurobiology of development and such influences continue to affect behavioral patterns and psychological outcomes in adulthood ( Roth, 2012 ). In addition, various external epigenetic factors modulate the biology of an individual at a physical and emotional level. Some of the most important exogenous factors influencing human health are described hereafter. We have described these influences in the “Adulthood” section for the sake of narrative simplicity, although they actually apply across the entire lifespan.

Studies in genomic imprinting have revealed how DNA methylation patterns are influenced by diet, and how epigenomic sensitivity to environmental cues and specifically diet can be used to influence disease susceptibility ( Waterland and Jirtle, 2003 ; Carone et al., 2010 ; Jennings and Willis, 2014 ).

Nutrients extracted from the diet enter metabolic pathways and are transformed into useful molecules. These nutrients are known to have epigenetic targets in cells such that they can be used to modify the epigenome in order to correct abnormally activated or silenced genes and can be combined into an “epigenetic diet” useful as a therapeutic or chemopreventive measure ( Hardy and Tollefsbol, 2011 ). During this transitory phase methyl groups are formed from key nutrients including folic acid, B vitamins and s-adenosyl methionine (SAMe), and these methyl groups, as described earlier, comprise important epigenetic marks for gene silencing. Diets high in such methyl rich nutrients may significantly alter gene expression and offer protective health benefits. Deficiencies in folate and methionine, both of which are involved in cellular processes that supply methyl groups needed for DNA methylation, can change the expression (imprinting) of growth factor genes such as (IGF1).

Folic acid. As explained earlier, DNA methylation can be used to distinguish a healthy CpG methylation profile from its inverted counterpart in tumor cells. Certain DNA repair genes including MGMT and MLH1 are prone to transcriptional silencing by promoter hypermethylation ( Jones and Baylin, 2002 ; Esteller, 2007 ). Variables including diet are capable of influencing epigenetic programing by altering DNA methylation and interfering with gene expression. Such potentially heritable modifications can be regulated by diet-responsive methylation. Specifically, deficient levels of folic acid lead to epigenetic alterations by inhibiting remethylation of s-adenosyl homocysteine (SAH) and s-adenosylmethionine (SAM) which results in demethylation and chromosome instability ( Dulthie, 2011 ). Thus, not only can dietary folate bolster a healthy locus-specific and global DNA methylation program, but can also direct proper uracil incorporation, inhibit DNA breakage, and foster DNA repair via thymidine and purine biosynthesis ( Ingrosso et al., 2003 ). Dietary folate present in a variety of green vegetables including broccoli, zucchini, brussels sprouts, green beans and spinach participates in maintaining a healthy DNA methylation profile and even reverses accrued damage ( Bhusari et al., 2010 ; Jennings and Willis, 2014 ).

Antioxidants and phytochemicals. Disruption in the balance between reactive oxygen species and antioxidants may result in harmful health effects caused by DNA damage due to the genotoxic effects of oxidative stress ( Waris and Ahsan, 2006 ). Foods are known to alter epigenetic expression in rats on different diets. Chemopreventive agents that target the epigenome include micronutrients found in folate, retinoic acid, selenium compounds, polyphenols from green tea, apples, coffee, black raspberries, and other dietary sources. Similar compounds are present in foods containing genistein and soy isoflavones, curcumin, and resveratrol to name a few ( Gerhauser, 2013 ). While certain food components epigenetically increase the levels of DNA repair enzymes such as MGMT and MLH1, others such as soy, isoflavones and bilberry anthocyanins actively decrease DNA damage ( Davis et al., 2001 ; Djuric et al., 2001 ; Olaharski et al., 2005 ; Fang et al., 2007 ; Kikuno et al., 2008 ; Burdge et al., 2011 ; Kropat et al., 2013 ). Anthocyanin is an effective antioxidant for humans that is found in plants and are easily identified by its potent red or purple pigment. It is found in plants such as eggplant, plums, pomegranate, red onion, cranberries, blueberries, kidney beans and cherries which all possess anthocyanins. This flavonoid serves as a powerful antioxidant that contributes to scavenging of DNA-damaging free radicals. While the direct fate of anthocyanins in vivo following digestion may be less than 5% (the majority being rapidly excreted), the potent residual antioxidant property remains in blood following consumption of anthocyanin-rich foods due to metabolic breakdown of the flavonoids and resultant increase in uric acid levels ( Williams et al., 2004 ; Lotito and Frei, 2006 ).

Another example is the polyphenol epigallocatechin-3-gallate (EGCG), which is contained in green tea and has been shown to retard carcinogenesis ( Fang et al., 2003 ). The pathway is similar to that used by other foods such as genistein in soy and involves regulation of DNA methylation at key genes to elicit positive epigenetic outcomes. Others like sulfopropanes from cruciferous vegetables and green tea can be used to treat age-related diseases and cancer since they are capable of reverting an aberrant epigenetic profile ( Tollefsbol, 2014 ). Other like sulfopropane form Owing to the numerous advantages that can be obtained through foods containing beneficial components and from probiotics, nutri- and microbial epigenetics is growing in importance because these bioactive molecules have been shown to be involved in regulating chromatin receptors and epigenome-related pathways ( Shenderov and Midtvedt, 2014 ).

Social interaction and behavior

There is no sharp edge dividing the biological from the behavioral aspects of epigenetic research. In fact there is a great deal of overlap. However, many interesting social perspectives contribute to the role of behavior on epigenetic modifications, and as such warrant a separate discussion since behavior is more readily controlled than biology. When mice were subjected to odor-fear conditioning prior to conception, increased behavioral sensitivity was observed in offspring in subsequent two generations ( Dias and Ressler, 2014 ). Epigenetic modifications complement the genome in that they do not change the DNA code directly, but influence it in such a way as to present it to the factors that read it and translate it into a final product. The ability to create, process and recall memory is reliant in part upon epigenetic modifications such as DNA remodeling ( Lattal and Wood, 2013 ). Nucleosome remodeling where histone-dependent nucleosomes are repositioned to expose DNA for gene expression is a factor in both healthy memory formation and cognitive impairment ( Malvaez et al., 2013 ; Vogel-Ciernia et al., 2013 ).

Exercise is one way that an individual can modify their epigenome in order to preserve and prolong life. Exercise has been shown to induce positive changes in DNA methylation within adipose tissue and regulate metabolism in both healthy and diseased individuals ( Ronn et al., 2013 ). Increased DNA methylation of genes Hdac4 and Ncor2 has also shown to increase lipogenesis following exercise ( Ronn et al., 2013 ). Exercise also leads to beneficial changes in DNA methylation patterns in skeletal muscle ( Nitert et al., 2012 ). Not only is obesity an indicator for diseases such as type 2 diabetes and cardiovascular disease, but also puts additional stress on the system which can itself negatively impact health ( Ronti et al., 2006 ). Acute exercise is associated with DNA hypomethylation of the entire genome in skeletal muscle cells of sedentary individuals and high intensity exercise tends to cause reduction in promoter methylation of certain genes ( Ntanasis-Stathopoulos et al., 2013 ). Exercise is also known to positively influence the expression patterns of miRNAs in leukocyte cells ( Radom-Aizik et al., 2010 ). The health benefits of physical exercise, especially on a long term and strenuous basis, has a positive effect on epigenetic mechanisms and ultimately may reduce incidence and severity of disease ( Sanchis-Gomar et al., 2012 ).

Pharmaceutical drugs

Pharmacoepigenetics is the study of inter-individual variations in epigenetic modifications as a result of prescribed pharmaceutical drug use. One working hypothesis is that exposure to therapeutic drugs may cause persistent epigenetic changes, possibly manifesting as permanent adverse side-effects ( Csoka and Szyf, 2009 ). There is a long list of drugs for which clinical or experimental evidence exists documenting either direct or indirect epigenetic effects (as described above). Direct effects are caused by drugs that interfere directly with the normal controls of DNA and/or histone methylation, resulting in aberrant gene expression. Indirect effects cause epigenetic changes by interaction with a cell surface receptor, enzyme, or other protein, which thereby alters expression of said receptors, and subsequently alters expression of transcription factors, which in turn change epigenetic regulation. Several epigenomic screening protocols are in place to identify drugs whose epigenetic power has therapeutic benefit and to isolate other drugs whose negative epigenetic impact outweighs potential benefit.

Drugs of abuse

Many drugs are used to enhance or alter the perception of reality and reward pleasure centers in the brain, but oftentimes these substances increase the risk of acute and/or chronic disease. Generally speaking, recreational drugs like cocaine but also including opiates, amphetamines, alcohol and nicotine modify the epigenome by altering methylation patterns in areas such as the nucleus accumbens of the brain, the major pleasure reward center ( Renthal and Nestler, 2008 ; Maze and Nestler, 2011 ; Doehring et al., 2013 ). Recreational drugs such as cocaine induce epigenetic changes in many ways, such as increasing histone acetylation on c-fos and fosb gene promoters ( Kumar et al., 2005 ). In terms of histone methylation, the epigenetic mark H3K9 been associated with chronic cocaine use, as well as with the process of cocaine addiction. Cocaine-induced plasticity is associated with the reduction in H3K9 methylation marks due to the repression of HMT G9a in the nucleus accumbens region of the brain ( Maze et al., 2010 ). Similarly, it has been demonstrated that pretreatment with histone deacetylase (HDAC) inhibitors helped in curbing cocaine addiction in animal models ( Romieu et al., 2011 ).

Smoking causes epigenetic changes such as DNA methylation changes, which alter gene expression. For example cigarette smoke induces demethylation of metastatic genes in lung cancer cells by downregulating DNMT3B ( Liu et al., 2007 ). DNA methylation is a type of epigenetic change that can result in tumor suppressor genes being inactivated, and methylation of the tumor suppressor gene p16 has frequently been associated with the development of cancer. When p16 is methylated, this gene's tumor suppressing function undergoes inactivation. This is why smoking is a major trigger for carcinogenesis. Of particular interest is the finding that not only maternal smoking but also grandmaternal smoking is linked to pediatric disease as a result of epigenetic changes to DNA and histones ( Rehan et al., 2012 ; Leslie, 2013 ) (See below for description of trans-generational influences).

Alcohol. The epigenetic effects of alcohol on hepatic and neuronal tissue are well documented ( Shukla et al., 2008 ). Ethanol is known to cause site-selective methylation, acetylation and phosphorylation of histones and DNA hypomethylation due to reduction of tissue SAM ( Shukla et al., 2008 ; Zakhari, 2013 ). One carbon metabolism (OCM) is a major methyl group donor, contributing toward DNA methylation and alcohol's interference with OCM leads to reduced availability of methyl groups and hence aberrant DNA methylation and gene expression in alcohol consumers ( Kruman and Fowler, 2014 ). A study with young mice showed that chronic alcohol exposure reduced global DNA hydroxymethylation in the liver as compared to control ( Tammen et al., 2014 ). Alcohol induced changes at the gastrointestinal- hepatic level like steatosis, carcinogenesis, endotexemia are also a result of epigenetic alterations ( Shukla and Lim, 2013 ).

Alcohol induced neuro-adaptations like tolerance and dependence are a result of epigenetic modulation at the neurobiological level ( Finegersh and Homanics, 2014a ). Acute ethanol exposure in mice leads to decreased expression of GAD1, HDAC2, HDAC11 associated with decreased histone acetylation at GAD1, HDAC2 promoters and increased expression of MT1, MT2, EGR1 associated with increased levels of H3K4me3 at MT2 promoter and decreased level of H3K27me3 at the MT1 promoter in the cerebral cortex ( Finegersh and Homanics, 2014a ).

Paternal alcohol exposure, prior to mating, has shown to induce increased sensitivity to anxiolytic and motor effects of alcohol, reduced alcohol preference and consumption exclusively in male offspring in mice ( Finegersh and Homanics, 2014b ). An increased expression of BDNF in the ventral tegmental area of such male offspring was also observed along with DNA hypomethyaltion of the BDNF promoter in the sire's germ cells and male and female offspring ( Finegersh and Homanics, 2014b ). Such effects are epigenetically transmitted through the male lineage and are capable of being a trans-generational influence. (See below for description of trans-generational influences.) Recent efforts toward elucidation of exact interactions between alcohol and the epigenome will help in developing treatments for alcohol-related disorders including fetal alcohol spectrum disorders, alcohol addiction and organ damage ( Shukla and Zakhari, 2013 ).

In recent years the interest in the identification of epigenetic marks associated with alcohol dependence has been growing ( Starkman et al., 2012 ). A major obstacle in this research is the limited number of candidate structural genes that might be participating in these pathways. However, DNA methylation in relation to alcohol use disorders has lately become a burning topic of research; a significant association between loss of control over drinking behavior and DNA methylation at multiple CpG sites has been observed, specifically methylation at CpG sites near the ALDH1A2 gene was found to be associated with rate of intoxication and inclination toward alcohol ( Harlaar et al., 2014 ).

Alternative medicine

Alternative medicine (AM) approaches like ayurverda, homeopathy, yoga, taichi, reiki, acupuncture, body massages, naturopathy, and hypnotherapy offer a promising approach toward improving human health and lifestyle by mediating beneficial environment-epigenome interactions (Figure 1 ). AM includes a variety of health practices, knowledge, beliefs and moreover therapeutic as well as spiritual techniques, which can be used to prevent or treat health conditions ( Report, 2001 ). One of the well-known forms of AM is Ayurveda, which has emphasized personalized health care for over 5000 years. Ayurvedic science advocates the use of herbs and spices in addition to foods for their medicinal properties, and their epigenetic effects have been identified. For example, tulsi and ginger regulate histone H3 acetylation and others spices such as turmeric and cinnamon possess similar effects ( Shim et al., 2011 ). Acupuncture, another form of AM, has been noted for its beneficial effects on cardiac health. Acupuncture therapy has been used for prevention of myocardial infarction (MI), strengthening of cardiovascular function and angiogenesis, and protection from further injury and apoptosis to myocardial cells after an MI ( He et al., 2014 ). This suggests how alternative medicine may operate through epigenetic regulation of regeneration, or cellular apoptosis in case of injury or degenerative diseases.

Environmental chemicals

Encounters with pesticides, toxins and synthetic compounds can methylate genes in adults and also promulgate diseases decades later in offspring following in utero exposures.

Heavy metals including arsenic, nickel and cadmium are widespread environmental contaminants capable of disrupting DNA methylation and histone acetylation and as a result have been associated with a number of diseases including cancer, neurological disorders and autoimmune diseases. Putative mechanisms may involve the fact that metals act as catalysts in the oxidative deterioration of biological macromolecules to produce free radicals and induce epigenetic changes ( Leonard et al., 2004 ; Babar et al., 2008 ; Monks et al., 2006 ).

Arsenic undergoes metabolic detoxification via methylation by S -adenosyl methionine (SAM), a universal methyl donor for methyltransferases (including DNMTs). Exposure to arsenic both decreases the activity of DNMTs and down regulates DNMT gene expression ( Reichard et al., 2007 ). Arsenic exposure induces hypermethylation of tumor suppressor genes ( Jensen et al., 2008 ), dysregulation of histone acetylation ( Hou et al., 2012 ), and promotion of micro RNA expression ( Marsit et al., 2006 ). Nickel is capable of compacting chromatin and methylating the DNA of tumor suppressor genes ( Lee et al., 1995 ). Exposure to nickel affects histone acetylation causing gene silencing and ultimately cell transformation ( Broday et al., 2000 ; Zhang and Zhu, 2012 ). Exposure to cadmium, mercury, lead, and chromium cause similar epigenetic modifications ( Takahashi et al., 2005 ; Huang et al., 2008 ; Sun et al., 2009 ; Wright et al., 2010 ; Arai et al., 2011 ).

Bisphenol A (BPA) and phthalates are plastics that leach into the environment. Not only are they estrogenic and known endocrine disruptors, but these chemicals and their metabolites also induce epigenetic modification in animal models ( Singh and Li, 2012 ). When ingested by humans, diethylhexyl phthalate (DEHP) is converted by intestinal lipases to mono-(2-ethylhexyl) phthalate (MEHP), which is then preferentially absorbed ( Morgan et al., 1999 ). Specifically, BPA disrupts DNA methylation by decreasing CpG methylation in the mouse agouti gene. This effect is reversible through dietary supplementation with a source of methyl donor groups such as folic acid and the phytoestrogen genistein (found in fava beans, soy beans, and coffee) ( Dolinoy et al., 2006 ).

Seasonal and diurnal changes

The operation of the circadian rhythm in humans is a result of temporal expression of clock controlled genes (CCGs) ( Sahar and Sassone-Corsi, 2012 ). Chromatin remodeling is the basis for differential expression of such CCGs through a 24-hour cycle, for example the epigenetic regulation Bmal1 (Figure 5 ). The drastic changes in lifestyle through the last century and higher incidence of modern day diseases like obesity, Type 2 diabetes and a spectrum of mental disorders has been linked to disruption of the internal circadian clock, a mechanism of homeostatic regulation of physiological processes and metabolic functions, and this has been attributed to exposure to epigenetic factors ( Orozco-Solis and Sassone-Corsi, 2014 ).

It is known that, unlike humans, the changes in season affect the reproductive behavior of seasonal breeding vertebrates as a physiological response to an altered photoperiod exposure. A study with Siberian hamsters showed that nocturnal pineal melatonin (MEL) protein is involved in DNA methylation changes of the promoter of dio3 gene, which is responsible for photoperiodic time measurement, and undergoes reversible epigenetic alterations for physiological orientation in time ( Stevenson and Prendergast, 2013 ).

Menopause is an event in a female's life that results in termination of her reproductive capability and is a gradual process accompanied by the deregulation of hormones ( Ubeda et al., 2014 ). Many genes are known to be epigenetically regulated during this process, like those implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG, and PRIM1) and immune function (IL11, NLRP11, and PRRC2A) ( Stolk et al., 2012 ). ENO1 is downregulated after menopause whereas TRIB2 and IGSF4 are up regulated ( Kosa et al., 2009 ) (Figure 6 ).

It is known that the DNA methylation status of Polycomb group target (PCGT) genes in endometrial tissue can be used as a biomarker to predict the risk for cancer development in premenopausal women ( Widschwendter et al., 2009 ). One of the members of the PCGT group, namely HOXA10, is highly expressed during implantation and is important for the process and its expression is reduced in patients with endometriosis ( Bagot et al., 2000 ; Wu et al., 2005 ). It was found that the global DNA methylation of eutopic endometrium in patients with endometriosis was higher as compared to ectopic endometrium of patients with endometriosis and a control group ( Andersson et al., 2014 ). Overall, aberrant DNA methylation leading to aberrant gene expression plays an important role in disease states of the endometrium and can cause additional changes to the process of menopause in females.

Aging and Age-Related Disease

Aging is a multifactorial process that results in a progressive loss of regenerative capacity through a decline in cell-proliferation and tissue functionality ( Campisi, 2013 ). It induces global and complex changes in the human DNA methylation landscape ( Xu and Taylor, 2014 ). Additional epigenetic changes have been described which provide clues to understanding the aging process. For example, senescent cells are characterized by formation of a specialized heterochromatin called senescence-associated heterochromatin foci that exhibit noticeable histone modifications ( Narita et al., 2003 ). These foci contribute to senescence-associated proliferation arrest that may silence the expression of proliferation-promoting genes ( Sedivy et al., 2008 ). Shortened telomeres, a hallmark of aging, may have reduced heterochromatin ( Benetti et al., 2007 ).

Genome-Wide DNA Methylation Changes

Generally, during the aging process, global hypomethylation of DNA occurs in a repetitive sequence pattern that may promote genomic instability ( Heyn et al., 2012 ). Not only is aging correlated with hypomethylation of proto-oncogenes, but also with hypermethylation of tumor suppressor genes, potentially leading to increased risk of cancer and other diseases ( Coppede, 2014 ).

Some methylation changes are so predictable that age-related DNA methylation patterns have been used to predict an individual's actual chronological age, such that DNA methylation can be used as a measure of age or age acceleration, as so-called “aging clock” ( Horvath, 2013 ).

Epigenetic changes in disease are not always focal, but can be global and encompass large chromosomal regions. For example the aberrant expression of micro RNAs has been linked to various age-related diseases such as Alzheimer's disease, cardiac disease and many cancers including leukemia and lymphoma ( Natarajan et al., 1992 ; Fabbri et al., 2009 ; Cheng and Zhang, 2010 ; Montgomery and Van Rooij, 2010 ; Provost, 2010 ), as described below.

Alzheimer's Disease

Alzheimer's disease is a neurodegenerative disorder characterized by β-Amyloid, inflammatory, oxidative and vascular damage. DNA hypomethylation of the entorhinal region of the cerebral cortex, plus hypermethylation and consequent overexpression of the hTERT gene have been reported in Alzheimer's research ( Silva et al., 2008 ; Mastroeni et al., 2010 ). Animal studies suggest that overexpression of histone deacetylase 2 (HDAC 2) may decrease synaptic plasticity and impair memory formation ( Guan et al., 2009 ; Urdinguio et al., 2009 ). Also, DNA methylation deficiency can accelerate age-related diseases and it has been shown that Dnmt1 haploinsufficiency can impair learning and memory function causing cognitive disorders with age ( Liu et al., 2011 ).

The epigenetic basis of osteoarthritis (OA) is seen in the fact that OA chondrocytes express genes involved in degradation of cartilage as a result of their hypomethylated promoters under the influence of cytokines like IL-1β and TNF-α, as opposed to normal chondrocytes ( Haseeb et al., 2014 ).

Cardiovascular Disease

Heart disease is often attributed to genetic predisposition, but epigenetic marks that vary between cell types and respond to endogenous and exogenous stimuli likely share culpability ( Ordovas and Smith, 2010 ). DNA methylation is critical for the development of atherosclerosis and cardiovascular disease; recently hypermethylation has been shown in differentially methylated genomic regions of patients suffering with coronoary artery disease (CAD) ( Sharma et al., 2014 ). DNA methyltransferases ( DNMT s) exhibit hypomethylation in mice, an observation associated with increased expression of inflammatory mediators ( Makar and Wilson, 2004 ). Also, DNA hypermethylation has been observed in the estrogen receptor genes ESR1 and ESR2 of vascular smooth muscle which contributes to atherosclerosis ( Lund and Zaina, 2011 ).

Not only is DNA methylation a primary regulator of inflammation, but also controls leukocyte functions related to cardiovascular risk ( Baccarelli et al., 2010 ). Removal of epigenetic signatures of oxidative and inflammatory genes has been proposed as a promising therapeutic option to prevent endothelial dysfunction and vascular complications in diabetic people ( Paneni et al., 2013 ).

Histone modification has also been implicated in various aspects of cardiovascular disease such as angiogenesis and myocardial infarction ( Webster et al., 2013 ). Histones are important for the normal regulation of the NOS3 gene. This gene codes for the protein eNOS that catalyzes formation of NO, a vasodilating factor in blood vessels that operates in the regulation of healthy cardiovascular tissue and can inhibit the ability of KDM3a protein to remove histone methyl groups ( Hickok et al., 2013 ).

Cancer has long been considered a disease of genetic origin, but an historic link between cancer and epigenetics was identified when DNA of colorectal cancer patients was observed to be hypomethylated ( Feinberg and Vogelstein, 1983 ). The normally hypermethylated and silent regions of the genome which contain repetitive sequences become demethylated. Conversely, hypermethylation of CpG islands in certain cancers is correlated with abnormal gene activity, such as deactivation of tumor suppressor genes ( Esteller, 2002 ). Hypermethylation of DNA also damages repetitive sequences of DNA called mircosatellites ( Oki et al., 1999 ); hypermethylation of the MLH1 promoter (a DNA repair gene) disfigures microsatellites, a phenomenon present in many cancers including colorectal and ovarian ( Jones and Baylin, 2002 ). These observations of promoter hypermethylation ( Coppede, 2014 ) and heterochromatinization ( Rideout et al., 1994 ) are compelling evidence of the dramatic influence of epigenetics on tumorigenesis.

A major locus susceptible to transcriptional silencing as a result of promoter hypermethylation is the INK4 locus located on chromosome 9 ( Kim and Sharpless, 2006 ). INK4 represents a family of cyclin-dependent kinase inhibitors. This gene encodes several proteins that are often targeted early during malignant progression, including p14, p15, and p16. Histone modification is another epigenetically important mechanism prevalent during carcinogenic transformation. Transcriptional control of p16 is interrupted when chromatin domains are lost and discrete histone structure is destroyed, in breast cancer cells for example ( Witcher and Emerson, 2009 ).

Epigenetic changes differ from their genetic counterparts such as gene mutations in that epigenetic hypermethylation affects many genes within a single cancer cell ( Coppede, 2014 ). For example, PIAS1, a transcriptional repressor, is involved in the progression of breast cancer and operates on an epigenetic level through gene silencing by recruting DNMTs ( Liu et al., 2014 ). Still, many researchers view the link between cancer and epigenetics with optimism, since epigenetic modifications are potentially reversible. For example, it is thought that cells harboring gene mutations must be killed or removed to prevent uncontrolled propagation of the damaged code. But advances in epigenetic technology may soon allow repair of defective epigenetic modifications by a variety of therapeutics. For example the drug azacitidine, the first FDA-approved epigenomic drug, treats leukemia by reactivating tumor suppressor genes and similar drugs are now in development ( Braiteh et al., 2008 ; Phillips, 2008 ).

Trans-Generational Influences

Many transgenerational phenotypic inheritance profiles cannot be explained by the normal human mutation rate of 2.3 × 10 −8 per nucleotide per generation ( Arnheim and Calabrese, 2009 ). The reason for this discrepancy is that epigenetic changes most likely contribute to the majority of these transgenerational effects.

Transgenerational epigenetic inheritance was first observed in plants ( Manning et al., 2006 ), however, it has also been reported in rodents and humans ( Carone et al., 2010 ). Heritability of epigenetic expression is demonstrable where multiple generations are simultaneously exposed to the same environmental conditions that include diet, toxins, hormones, etc. ( Curley et al., 2011 ; Vassoler et al., 2013 ). In such a model, the mother = first generation, the fetus = 2nd generation, the reproductive cells of fetus = 3rd generation, and the future offspring of fetus = 4th generation. In order to provide a convincing case for trans-generational stability, an epigenetic change must be observed in the 4th generation ( Hughes, 2014 ). Recent studies have shown that maternal methyl-donor supplementation affects not only the mother, but is also inherited in the F2 generation through germline epigenetic modifications ( Duhl et al., 1994 ; Wolff et al., 1998 ; Morgan et al., 1999 ; Cropley et al., 2006 ). Transgenerational epigenetic influence of longevity has also been shown in C. elegans ( Greer et al., 2011 ).

Epigenetics in Translational and Personalized Medicine

For the past several decades genetics has been at the forefront in terms of understanding human disease. A recent addition to genetics has been epigenetics, which includes the role of the environment, both social and natural, including day-to-day habits, lifestyle and personal experiences on human health. Epigenetics establishes a scientific basis for how external factors and the environment can shape an individual both physically and mentally.

The knowledge that environment and lifestyle can alter health brings with it awareness that habits, social environment, diet and other factors shape health beyond our acquired genetic traits. Moreover, despite the risk presented by inherited genes and mutations, epigenetic factors play a decisive role in the actual development of disease. Research into epigenetics could lead to insights into how factors like diet and exercise can be customized to an individual in concordance with their naturally inherited genome in order to minimize the risk of developing a disease to which he/she is naturally predisposed.

Advances in epigenetic profiling technology such as genome-scale DNA methylation analysis points to the future possibilities of how epigenetic profiling can help in determining the risk of an individual with a particular type of genetic makeup developing a specific disease. Also the same epigenetic profile, along with knowledge of the genomic sequence, can help to determine which medications or alternative medicine approaches would be effective in preventing or curing a particular disease. Such approaches toward improving health and lifestyle and reducing the risk of developing an otherwise inevitable disease might be possible in the near future. It will require extensive knowledge of the biochemical and physiological mechanisms of epigenetics, and we are still on this challenging path, but we have good reasons to be optimistic.

Conclusions

We have presented a comprehensive narrative of the role of both endogenous and exogenous epigenetic influences on the human lifespan.

The future of epigenetics holds tremendous promise for understanding the complexities involved in genetic regulation, cellular differentiation, aging and disease; and a more complete and comprehensive understanding of the mechanisms that underlie the formation and erasure of epigenetic marks could allow us to commandeer the process and possibly fine tune the human epigenome.

Ultimately, continued efforts to determine how and when epigenetic switches regulate gene function will elucidate the interplay between the genome, the epigenome, and the environment and facilitate the development and optimization of novel therapeutic tools. In terms of future application, full understanding of these mechanisms will ultimately revolutionize personalized medicine.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgment

The Authors would like to thank Dr. Donald Orlic for critical review of the manuscript.

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Keywords: epigenetics, human lifespan, disease, environment, diet, development

Citation: Kanherkar RR, Bhatia-Dey N and Csoka AB (2014) Epigenetics across the human lifespan. Front. Cell Dev. Biol . 2 :49. doi: 10.3389/fcell.2014.00049

Received: 20 June 2014; Accepted: 22 August 2014; Published online: 09 September 2014.

Reviewed by:

Copyright © 2014 Kanherkar, Bhatia-Dey and Csoka. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Antonei B. Csoka, Epigenetics Laboratory, Department of Anatomy, Howard University, 520 W St. NW, Mudd 431, Washington, DC 20059, USA e-mail: [email protected]

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Epigenetics, Health, and Disease

What to know.

Epigenetics refers to the way your behaviors and environment can cause changes that affect the way your genes work. Epigenetics turns genes "on" and "off." Your epigenetics change as you age, both as part of normal development and aging and because of exposure to environmental factors that happen over the course of your life. Epigenetic changes can affect your health in different ways.

Your genes play an important role in your health, but so do your behaviors and environment, such as what you eat and how physically active you are. Epigenetics refers to how your behaviors and environment can cause changes that affect the way your genes work. Unlike genetic changes (mutations), epigenetic changes are reversible and do not change the sequence of DNA bases, but they can change how your body reads a DNA sequence.

Gene expression refers to the process of making proteins using the instructions from genes. A person's DNA includes many genes. Each gene includes instructions for making proteins. Additionally, there are other sections of DNA that are not part of any gene but are important for making sure the genes work properly. These DNA sections provide directions about where in the body the protein is made, when it is made, and how much is made.

While changes to the genes (mutations) can change the protein that is made, epigenetic changes affect gene expression to turn genes "on" and "off." This can mean that genes make proteins in cells and tissues where or when they normally would not, or that genes don't make proteins where and when they normally would. It can also mean that genes make more or less of a protein than they normally would.

There are several ways an environmental factor can cause an epigenetic change to occur. One of the most common ways is by causing changes to DNA methylation. DNA methylation works by adding a chemical (known as a methyl group) to DNA. This chemical can also be removed from the DNA through a process called demethylation. Typically, methylation turns genes off and demethylation turns genes on. Thus, environmental factors can impact the amount of protein a cell makes. Less protein might be made if an environmental factor causes an increase in DNA methylation, and more protein might be made if a factor causes an increase in demethylation.

Epigenetics and age

Your epigenetics change as you age as part of normal development.

Epigenetics and development

Epigenetic changes begin before you are born. All your cells have the same genes but look and act differently. As you grow and develop, epigenetics helps determine which function a cell will have—for example, whether it will become a heart cell, nerve cell, muscle cell, or skin cell.

EXAMPLE: Nerve cell and muscle cell. Your nerve cells and muscle cells have the same DNA, but they work differently. A nerve cell transports information to other cells in your body. A muscle cell has a structure that aids in your body's ability to move. Epigenetics allows the muscle cell to turn on genes to make proteins important for its job and turn off genes important for a nerve cell's job.

Your epigenetics change throughout your life. Your epigenetics at birth are not the same as your epigenetics during childhood or adulthood.

EXAMPLE: A newborn, 26-year-old, and 103-year-old. Scientists measured DNA methylation at millions of sites in a newborn, 26-year-old, and 103-year-old. The level of DNA methylation decreased with age. The newborn had the highest level of DNA methylation, the 103-year-old had the lowest level of DNA methylation, and the 26-year-old had a DNA methylation level that was between that of the newborn and the 103-year-old. 1

Epigenetics and exposures

Your epigenetics can change in response to your behaviors and environment.

Nutrition during pregnancy

A pregnant person's environment and behavior during pregnancy, such as whether they eat healthy food, can change the baby's epigenetics. Some of these changes can remain for decades and might make the child more likely to get certain diseases.

EXAMPLE: Dutch Hunger Winter famine (1944 – 1945). People whose mothers were pregnant with them during the famine were more likely to develop certain diseases, such as heart disease, schizophrenia, and type 2 diabetes. 2 Around 60 years after the famine, researchers looked at DNA methylation levels in people whose mothers were pregnant with them during the famine. These people had increased DNA methylation at some genes and decreased DNA methylation at other genes, compared with their siblings who were not exposed to famine before birth. 3 4 5 These differences in DNA methylation could help explain why these people had an increased likelihood for certain diseases later in life. 2 5 6 7

Exposures such as smoking can cause epigenetic changes. However, these epigenetic changes can be reversible in some cases.

EXAMPLE: Smokers, nonsmokers, and former smokers. Smoking can result in epigenetic changes. For example, at certain parts of the AHRR gene, smokers tend to have less DNA methylation than nonsmokers. The difference is greater for heavy smokers and long-term smokers. After quitting smoking, former smokers can begin to have increased DNA methylation at this gene. Eventually, they can reach levels similar to those of nonsmokers. In some cases, this can happen in less than a year, but the length of time depends on how long and how much someone smoked before quitting. 8

Epigenetics and diseases

Certain diseases can change your epigenetics. In addition, some epigenetic changes can make you more likely to develop certain diseases, such as cancer.

Germs can change your epigenetics to weaken your immune system. This helps the germ survive.

EXAMPLE: Tuberculosis. Mycobacterium tuberculosis causes tuberculosis. Infections with these germs can cause epigenetic changes in some of your immune cells that result in turning off the IL-12B gene. Turning off the IL-12B gene weakens your immune system and improves the survival of Mycobacterium tuberculosis. 9

Certain mutations make you more likely to develop cancer. Likewise, some epigenetic changes increase your cancer risk. For example, having a mutation in the BRCA1 gene that prevents it from working properly makes you more likely to get breast and other cancers. Similarly, increased DNA methylation that results in decreased BRCA1 gene expression raises your risk for breast and other cancers. 10 While cancer cells have increased DNA methylation at certain genes, overall DNA methylation levels are lower in cancer cells compared with normal cells.

Different types of cancer that seem similar can have different DNA methylation patterns. Epigenetics can be used to help determine which type of cancer a person has or can help to find hard-to-detect cancers earlier. Epigenetics alone cannot diagnose cancer. Cancers would need to be confirmed with further screening tests.

EXAMPLE: Colorectal cancer. Colorectal cancers have abnormal DNA methylation near certain genes, which affects expression of these genes. Some commercial colorectal cancer screening tests (for example, Cologuard ® ) use stool samples to look for this abnormal DNA methylation. It is important to know that if you have one of these tests and the result is positive or abnormal, you will need to have a colonoscopy, which is a procedure to check your colon for cancer. 11

Learn. Genetics: Genetic Science Learning Center at the University of Utah provides a detailed explanation and interactive tutorial about epigenetics.
National Human Genomic Research Institute: Epigenomics Fact Sheet provides answers to questions about the epigenome.
National Institute of Environmental Health Sciences: Epigenetics provides information about epigenetics, epigenetic research, and a video about epigenetics.
Distinct DNA methylomes of newborns and centenarians . Proc Natl Acad Sci U S A 2012; 109:10522-7. Heyn H, Li N, Ferreira H, et al.
Epidemiological evidence for the developmental origins of health and disease: effects of prenatal undernutrition in humans . J Endocrinol 2019. 242:T135-T144. Roseboom T.
Persistent epigenetic differences associated with prenatal exposure to famine in humans . Proc Natl Acad Sci U S A 2008; 105: 17046-17049. Heijmans B, Tobi E, Stein A, et al.
DNA Methylation Differences After Exposure to Prenatal Famine Are Common and Timing- And Sex- Specific . Hum Mol Genet 2009; 18:4046-53. Tobi E, Lumey L, Talens R, et al.
DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood . Sci Adv 2018; 4:eaao4364. Tobi E, Slieker R, Luijk R, et al.
DNA Methylation of Loci Within ABCG1 and PHOSPHO1 in Blood DNA is Associated With Future Type 2 Diabetes Risk . Epigenetics 2016; 7: 482-8. Dayeh T, Tuomi T, Almgren P, et al.
Epigenetic and genetic variation at the IGF2/H19 imprinting control region on 11p15.5 is associated with cerebellum weight . Epigenetics 2012; 7:155-163. Pidsley R, Dempster E, Troakes C, et al.
Epigenetic signatures of starting and stopping smoking . EBioMedicine 2018; 37:214-220. McCartney D, Stevenson A, Hillary R, et al.
Mycobacterium tuberculosis Infection Induces HDAC1-Medicated Suppression of IL-12B Gene Expression in Macrophages . Front Cell Infect Microbiol 2015; 5:90. Chandran A, Antony C, Jose L, et al.
Blood-based DNA methylation as biomarker for breast cancer: a systematic review . Clin Epigenetics 2016; 8: 115. Tang Q, Cheng J, Cao X, et al.
Advances in tests for colorectal cancer screening and diagnosis . Expert Rev Mol Diagn 2022; 22: 449-460. Chan SCH, Liang JQ.

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Genetics, epigenetic mechanism.

Nora M. Al Aboud ; Connor Tupper ; Ishwarlal Jialal .

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Last Update: August 14, 2023 .

Introduction

Epigenetics is the study of heritable and stable changes in gene expression that occur through alterations in the chromosome rather than in the DNA sequence. [1] Despite not directly altering the DNA sequence, epigenetic mechanisms can regulate gene expression through chemical modifications of DNA bases and changes to the chromosomal superstructure in which DNA is packaged.

Briefly, negatively charged DNA is packaged around a positively charged histone protein octamer, which contains 2 copies of histone proteins H2A, H2B, H3, and H4. [2] This nucleoprotein complex is a nucleosome, the basic unit of chromatin. [3] The nucleosomes of a continuous DNA polymer are connected by linker DNA and the complex is stabilized by histone protein H1. The aggregation of chromatin results in the formation of a chromosome. The chromatin of a chromosome exists as either loose, transcriptionally active euchromatin or dense, transcriptionally inactive heterochromatin. [4] Chemical alterations to histone proteins can induce the formation of either the open euchromatin state, which facilitates gene expression by allowing transcription factors and enzymes to interact with the DNA, or the closed heterochromatin state, which suppresses gene expression by preventing initiation of transcription.

In addition to histone changes, DNA methylation is an epigenetic mechanism associated with gene silencing when the methylation occurs in CpG islands of promoter sequences. [5] Further, non-coding RNA sequences have shown to play a key role in the regulation of gene expression. [6] These epigenetic modifications can be induced by several factors including age, diet, smoking, stress, and disease state. [7] [8] Epigenetic modifications are reversible, but they rarely remain through generations in humans despite persisting through multiple cycles of cell replication. [9]

Epigenetic mechanisms form a layer of control within a cell that regulates gene expression and silencing. This control varies between tissues and plays an important role in cell differentiation. [10] Additionally, differences in gene expression between cells, which are driven by epigenetic modifications, result in the unique function of specific cell types. [11] Genome-wide patterns of DNA and histone modifications are established during early development and are maintained throughout multiple cell divisions. In cancer, the normal epigenetic patterns are disrupted resulting in the expression of anti-apoptotic and pro-proliferative genes and silencing of tumor suppressor genes like CDKN2A. [12]

Three different epigenetic mechanisms have been identified: DNA methylation, histone modification, and non-coding RNA (ncRNA)-associated gene silencing. Catalyzed by DNA methyltransferase enzymes, DNA methylation involves the addition of a methyl group directly to a cytosine nucleotide within a cytosine-guanine sequence (CpG), which are often surrounded by other CpG’s forming a CpG island. CpG islands are common targets for epigenetic DNA methylation, notably the CpG islands within promoter regions. Indeed, it has been reported that around 70% of gene promotor regions lie within CpG islands. [13] Methylated cytosines within a promoter region recruit gene suppressor proteins and reduce interaction between the DNA and transcription factors. [14] Cytosine methylation also drives the formation of heterochromatin, so the nucleosome tightening prevents transcriptional machinery from interacting with the DNA. [15] As such, DNA methylation within promoter regions results in gene silencing. Cancers often show marked hypermethylation of tumor suppressor genes and hypomethylation of proto-oncogenes, both of which contribute to tumor carcinogenesis. [15] This epigenetic mechanism also plays an important role in tissue-specific gene regulation, genomic imprinting, and X chromosome inactivation. [14]

The second epigenetic mechanism is post-translational modifications to histone proteins. These modifications include enzyme-catalyzed acetylation, methylation, phosphorylation, and ubiquitylation, each of which alters the DNA-histone interactions in nucleosomes. [16] Histone acetylation often occurs at positively charged lysine residues which weakens the DNA-histone interactions, thus opening the chromatin and facilitating transcription. [17] For example, acetylation of lysine 9 and lysine 27 on histone 3 (H3K9ac and H3K27ac, respectively) correlates with transcription activation. Histone methylation is more complex as it does not change the histone protein charge and can include the addition of 1-3 methyl groups to lysine and 1-2 methyl groups to arginine. [17] For example, methylation of lysine 4 on histone 3 (H3K4me) is associated with transcription activation while trimethylation of lysine 27 on histone 3 (H3K27me3) correlates with transcription repression. [18] Histone phosphorylation involves the addition of a negative phosphate group to the histone tail, but less is known of its function aside from phosphorylation of H2A(X) playing a role in the response to DNA damage and its subsequent repair. [19] Histone ubiquitylation involves the addition of a large ubiquitin molecule to lysine residues. Examples of histone ubiquitylation include H2AK119ub, which is associated with gene silencing, and H2BK123ub, which is involved in transcription. [17] Aside from the relatively straightforward effect of histone acetylation on gene expression, the effects of other histone modifications are complex and greatly influenced by the state of nearby DNA molecules.

The most recently elucidated epigenetic mechanism is non-coding RNA-associated gene silencing. A non-coding RNA (ncRNA) is a functional RNA molecule that is transcribed but not translated into proteins. Once regarded as waste of the genome, recent insight suggests the ncRNA molecules harbor a crucial role in epigenetic gene expression and likely account for the great difference in phenotype between species and within human populations despite such similarity in encoded proteins. [6] [18] Notable ncRNA molecules include microRNAs (miRNA) and short interfering RNAs (siRNA), which include less than 30 nucleotides, and long non-coding RNAs (lncRNA), which are 200 nucleotides or longer. Though the full extent of their role in epigenetics is still being determined, there is evidence suggesting that ncRNAs participate in DNA methylation and histone modifications in addition to gene silencing. [20] siRNAs and lncRNAs both have been shown to regulate gene expression by the formation of heterochromatin. [6] [21]

Clinical Significance

As people age, the largest influence on the epigenome is the environment. Direct influencers such as diet can affect one's epigenome, as determined by the Dutch famine studies. [22] [23] Other environmental stressors include smoking and psychological stress. Epigenetic changes in utero are particularly sensitive as the epigenetic profile of the fetus is forming and developing rapidly during this time. [24] Indeed, teratogens like cigarette smoke, alcohol, and specific minerals have shown to induce in utero epigenetic changes. [24] [25]

Perhaps the most studied clinical application of epigenetic mechanisms is cancer. One of the first reports of epigenetics involved in cancer reported hypomethylation of DNA in cancer cell genomes, which caused overexpression of genes within that cell. [26] Since this report, great strides have been made toward understanding the role of epigenetics in carcinogenesis. For example, the degree of DNA methylation continues to decrease as a benign tumor cell progresses to invasive cancer. [27] Other studies have shown hypomethylation of pro-proliferative genes like BAX2 that are suppressed in normal cells. [28] Other reports show hypermethylation of tumor suppressor genes, like Rb, BCRA1, and CDKN2A, in cancer cells. [29] [30] [31] Despite the wealth of knowledge present on the relationship between epigenetics and carcinogenesis, treatment development is still very much in the preliminary phase for most cancers.

Epigenetics is a promising field of research because of the potential to regulate gene expression without changing the DNA sequence, which may likely cause safety and ethical concerns if performed in humans. The most promising way to treat diseases through epigenetic regulation has been through pharmacology. Previous clinical trials for drugs formulated to block epigenetic modifications associated with cancers have proved successful. The FDA has approved a number of these drugs which target epigenetic regulators to treat various cancers including azacytidine and decitabine for myelodysplastic syndrome, panobinostat for multiple myeloma, and romidepsin for cutaneous T cell lymphoma. [32] More drugs are likely to be approved in the coming years as a number of clinical trials for DNA methylation inhibitors and histone modification inhibitors are underway.

In addition to cancers, many conditions associated with genomic imprinting are the result of malfunctioning epigenetic mechanisms. Epigenetic mechanisms can induce disease, but they are also necessary for normal cell function, specifically in imprinted genes where only one parental chromosome is expressed. For genomic imprinting to successfully occur, the other parental chromosome must be silenced, which occurs through DNA methylation. Noteworthy conditions associated with abnormalities in gene imprinting include Prader-Willi syndrome, Angelman syndrome, Beckwith-Wiedemann syndrome, Russell-Silver syndrome, and Rubenstein-Taybi syndrome. [33] [34] Recent studies have shown positive results for epigenetic-based therapies for imprinting disorders, which may be a field of increased focus in the coming years in search of better treatments. [35] [36]

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Published: 20 May 2024

In vitro reconstitution of epigenetic reprogramming in the human germ line

Yusuke Murase 1 , 2 na1 ,
Ryuta Yokogawa ORCID: orcid.org/0000-0002-7033-2794 1 , 2 na1 ,
Yukihiro Yabuta 1 , 2 ,
Masahiro Nagano 1 , 2 ,
Yoshitaka Katou 1 , 2 ,
Manami Mizuyama ORCID: orcid.org/0009-0003-3971-2996 1 , 2 ,
Ayaka Kitamura 1 , 2 ,
Pimpitcha Puangsricharoen 1 , 2 ,
Chika Yamashiro ORCID: orcid.org/0000-0001-7412-6341 2 ,
Bo Hu 1 , 2 ,
Ken Mizuta ORCID: orcid.org/0000-0002-3922-1009 1 , 2 ,
Kosuke Ogata ORCID: orcid.org/0000-0002-0634-3990 3 ,
Yasushi Ishihama ORCID: orcid.org/0000-0001-7714-203X 3 &
Mitinori Saitou ORCID: orcid.org/0000-0002-2895-6798 1 , 2 , 4

Nature ( 2024 ) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Embryonic germ cells
Germline development

Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia, ensuring sexually dimorphic germ-cell development for totipotency 1 . In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here, we establish a robust strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem cell (PSC)-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (~>10 10 -fold). Strikingly, bone morphogenetic protein (BMP) signalling is a key driver of these processes: BMP-driven hPGCLC differentiation involves an attenuation of the mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK) pathway and both de novo and maintenance DNA methyltransferase (DNMT) activities, likely promoting replication-coupled, passive DNA demethylation. On the other hand, hPGCLCs deficient in tens-eleven translocation (TET) 1, an active DNA demethylase abundant in human germ cells 2,3 , differentiate into extraembryonic cells, including amnion, with de-repression of key genes bearing bivalent promoters; these cells fail to fully activate genes vital for spermatogenesis and oogenesis, with their promoters remaining methylated. Our study elucidates the framework of epigenetic reprogramming in humans, making a fundamental advance in human biology, and through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, represents a milestone for human in vitro gametogenesis (IVG) research and its potential translation into reproductive medicine.

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These authors contributed equally: Yusuke Murase, Ryuta Yokogawa

Authors and Affiliations

Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan

Yusuke Murase, Ryuta Yokogawa, Yukihiro Yabuta, Masahiro Nagano, Yoshitaka Katou, Manami Mizuyama, Ayaka Kitamura, Pimpitcha Puangsricharoen, Bo Hu, Ken Mizuta & Mitinori Saitou

Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan

Yusuke Murase, Ryuta Yokogawa, Yukihiro Yabuta, Masahiro Nagano, Yoshitaka Katou, Manami Mizuyama, Ayaka Kitamura, Pimpitcha Puangsricharoen, Chika Yamashiro, Bo Hu, Ken Mizuta & Mitinori Saitou

Department of Molecular Systems BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

Kosuke Ogata & Yasushi Ishihama

Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan

Mitinori Saitou

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Correspondence to Mitinori Saitou .

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Murase, Y., Yokogawa, R., Yabuta, Y. et al. In vitro reconstitution of epigenetic reprogramming in the human germ line. Nature (2024). https://doi.org/10.1038/s41586-024-07526-6

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DOI : https://doi.org/10.1038/s41586-024-07526-6

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