Series 01 January 2018

Epigenetics

Techniques that interrogate DNA methylation, histone modifications or chromatin conformations are enabling unprecedented analyses of epigenomes, including at the single-cell level. The articles in this series discuss insights into chromatin biology and the components and mechanisms of diverse epigenetic processes in health and disease, from fundamental roles in gene regulation to broader biological phenomena such as reprogramming, imprinting and transgenerational inheritance.

Content

DNA methylation-based predictors of health: applications and statistical considerations

DNA methylation-based predictors of health aim to predict outcomes such as exposure, phenotype or disease on the basis of genome-wide levels of DNA methylation. The authors review applications of existing DNA methylation-based predictors and highlight key statistical best practices to ensure their reliable performance.
- Paul D. Yousefi
- Matthew Suderman
- Caroline L. Relton
Review Article18 Mar 2022 Nature Reviews Genetics
Molecular mechanisms of transgenerational epigenetic inheritance

In this Review, Fitz-James and Cavalli discuss the diverse and often multilayered mechanisms by which transgenerational epigenetic inheritance can occur in different species.
- Maximilian H. Fitz-James
- Giacomo Cavalli
Review Article4 Jan 2022 Nature Reviews Genetics
Interplay between chromatin marks in development and disease

In this Review, Janssen and Lorincz discuss the intricate and multilayered interplay between chromatin marks. Focusing on histone methylation and DNA methylation during mammalian development, they discuss the implications for gene regulation, differentiation and human disease.
- Sanne M. Janssen
- Matthew C. Lorincz
Review Article4 Oct 2021 Nature Reviews Genetics
Epigenome plasticity in plants

The authors review intra-individual and inter-individual plant epigenome variation during development and in response to environmental changes, including stress. They also discuss functions of epigenome plasticity and epigenome editing technologies that will drive future research.
- James P. B. Lloyd
- Ryan Lister
Review Article15 Sep 2021 Nature Reviews Genetics
The epigenetic basis of cellular heterogeneity

In this Review, Carter and Zhao discuss how single-cell sequencing technologies are being applied to investigate epigenetic heterogeneity among seemingly homogeneous populations of cells and how this epigenetic variability relates to cell–cell differences in gene expression.
- Benjamin Carter
- Keji Zhao
Review Article26 Nov 2020 Nature Reviews Genetics
Active turnover of DNA methylation during cell fate decisions

Recent studies have demonstrated that concomitant activity of de novo methylation and demethylation machineries results in rapid turnover of DNA methylation in certain contexts. The authors review this phenomenon and propose that DNA methylation turnover may facilitate key lineage decisions.
- Aled Parry
- Steffen Rulands
- Wolf Reik
Perspective6 Oct 2020 Nature Reviews Genetics
COMPASS and SWI/SNF complexes in development and disease

In this Review, Cenik and Shilatifard focus on two families of Trithorax group proteins: COMPASS histone H3 lysine 4 methyltransferase complexes and SWI/SNF chromatin remodelling complexes. They discuss the roles of these complexes in gene regulation, development and disease.
- Bercin K. Cenik
- Ali Shilatifard
Review Article21 Sep 2020 Nature Reviews Genetics
The evolving metabolic landscape of chromatin biology and epigenetics

Various cellular metabolites provide the chemical moieties for DNA and histone modifications, resulting in a complex interplay between metabolism and epigenetics. In this Review, Dai, Ramesh and Locasale discuss the metabolic regulation of diverse types of chromatin modifications and the functional consequences of these modifications at the molecular, cellular and organismal levels, as well as influences from diet and microbiota.
- Ziwei Dai
- Vijyendra Ramesh
- Jason W. Locasale
Review Article9 Sep 2020 Nature Reviews Genetics
Chromatin-associated RNAs as facilitators of functional genomic interactions

Enabled by genome-wide profiling approaches, there is growing appreciation for the prevalence and functional importance of various types of chromatin-associated RNAs. As Li and Fu describe in this Review, these RNAs can either be retained in cis at their site of transcription or recruited in cis to other loci, and they have diverse roles in gene regulation, genome organization, nuclear body formation and phase-separation events.
- Xiao Li
- Xiang-Dong Fu
Review Article3 Jun 2019 Nature Reviews Genetics
Long-range enhancer–promoter contacts in gene expression control

For appropriate control of gene expression, enhancers must communicate with the right target genes at the right time, typically over large genomic distances. In this Review, Schoenfelder and Fraser discuss our latest understanding of long-range enhancer–promoter crosstalk, including target-gene specificity, interaction dynamics, protein and RNA architects of interactions, roles of 3D genome organization and the pathological consequences of regulatory rewiring.
- Stefan Schoenfelder
- Peter Fraser
Review Article13 May 2019 Nature Reviews Genetics
Old cogs, new tricks: the evolution of gene expression in a chromatin context

Eukaryotes differ substantially from bacteria and archaea owing to their nucleosome-based packaging of DNA. In this Review, Talbert, Meers and Henikoff place gene regulation in an evolutionary context by discussing how the emergence and diversification of eukaryotic chromatin provided both challenges and opportunities for intricate mechanisms of gene regulation in eukaryotes.
- Paul B. Talbert
- Michael P. Meers
- Steven Henikoff
Review Article18 Mar 2019 Nature Reviews Genetics
Chromatin accessibility and the regulatory epigenome

Chromatin accessibility comprises the positions, compaction and dynamics of nucleosomes, as well as the occupancy of DNA by other proteins such as transcription factors. In this Review, the authors discuss diverse methods for characterizing chromatin accessibility, how accessibility is determined and remodelled in cells and the regulatory roles of accessibility in gene expression and development.
- Sandy L. Klemm
- Zohar Shipony
- William J. Greenleaf
Review Article23 Jan 2019 Nature Reviews Genetics
Deciphering bacterial epigenomes using modern sequencing technologies

DNA methylation is the primary epigenetic modification in bacteria, but a lack of suitable methods has hampered its study. Now, new sequencing technologies, including single-molecule, real-time sequencing and nanopore sequencing, are providing new opportunities for studying bacterial methylomes.
- John Beaulaurier
- Eric E. Schadt
- Gang Fang
Review Article13 Dec 2018 Nature Reviews Genetics
Clinical epigenetics: seizing opportunities for translation

Disruptions to the epigenome occur during the pathogenesis of various human diseases. In this Review, Berdasco and Esteller describe the challenges and progress of harnessing epigenetic changes for clinical application, including for diagnostics, disease classification and therapeutics. They discuss applications to diverse diseases, such as cancer, neurological disease, immune disorders and viral infections.
- María Berdasco
- Manel Esteller
Review Article27 Nov 2018 Nature Reviews Genetics
Organizational principles of 3D genome architecture

High-resolution studies of chromosome conformation are revealing that the 3D genome is organized into smaller structural features than was previously supposed and is primarily composed of compartmental domains and CTCF loops. In this Perspectives article Rowley and Corces describe the latest views on the organizational drivers and principles of the 3D genome, and the interplay between genome activity and organization.
- M. Jordan Rowley
- Victor G. Corces
Perspective26 Oct 2018 Nature Reviews Genetics
DNA methylation-based biomarkers and the epigenetic clock theory of ageing

Biomarkers of ageing based on DNA methylation data enable accurate age estimates for any tissue across the entire life course. Horvath and Raj review the development of these ‘epigenetic clocks’ and how they link to biological ageing.
- Steve Horvath
- Kenneth Raj
Review Article11 Apr 2018 Nature Reviews Genetics
Statistical and integrative system-level analysis of DNA methylation data

The wealth of DNA methylation data continues to grow rapidly, including from epigenome-wide association studies (EWAS). However, extracting meaningful biological and clinical information requires diverse computational approaches for data analysis. This Review discusses the range of statistical tools available, including for cell-type deconvolution, identification of important methylation data features, causation and system-level integration with other types of omic data.
- Andrew E. Teschendorff
- Caroline L. Relton
Review Article13 Nov 2017 Nature Reviews Genetics
The interplay of epigenetic marks during stem cell differentiation and development

Cell state transitions during embryonic development are associated with epigenetic changes that alter chromatin structure and gene expression. Interplay between epigenetic regulatory layers can be studied using genomic technologies and embryonic stem cell cultures that reflectin vivocell states.
- Yaser Atlasi
- Hendrik G. Stunnenberg
Review Article14 Aug 2017 Nature Reviews Genetics
The DNA methyltransferase family: a versatile toolkit for epigenetic regulation

The DNA methyltransferase (DNMT) family comprises a conserved set of DNA-modifying enzymes. Recent studies have increased our understanding of how DNMT activity is regulated and revealed that, in addition to establishing and maintaining DNA methylation patterns, DNMT enzymes function in transcriptional silencing, transcriptional activation and post-transcriptional regulation.
- Frank Lyko
Review Article16 Oct 2017 Nature Reviews Genetics
Dynamic chromatin technologies: from individual molecules to epigenomic regulation in cells

A full understanding of chromatin in diverse cellular processes requires the consideration of its dynamics, but most standard chromatin assays provide only a static snapshot. This Review describes various emerging methods for probing chromatin dynamics across a wide range of temporal and spatial scales, and discusses the resulting biological insights.
- Olivier Cuvier
- Beat Fierz
Review Article22 May 2017 Nature Reviews Genetics
Exploiting induced and natural epigenetic variation for crop improvement

To unlock the potential of epigenetic variation for crop improvement, it will be crucial to understand how epigenetic variation is established and how it is stably inherited across generations. Springer and Schmitz review these challenges, the different sources of epigenetic variation in plants, and how epigenome profiling and engineering could help to improve crops.
- Nathan M. Springer
- Robert J. Schmitz
Review Article3 Jul 2017 Nature Reviews Genetics
Associating cellular epigenetic models with human phenotypes

Epigenome-wide association studies (EWAS) are potentially powerful approaches for identifying transcriptional regulatory perturbations (particularly DNA methylation) that associate with phenotypes of interest. In this Opinion article, Lappalainen and Greally provide their views on how to maximize the interpretability and biological insights from these associations, such as by hypothesis-driven consideration of cellular phenotypes, characterizing the roles of transcription factors, dissecting directions of causality and moving towards multi-omics profiling.
- Tuuli Lappalainen
- John M. Greally
Opinion30 May 2017 Nature Reviews Genetics
TET-mediated active DNA demethylation: mechanism, function and beyond

A key mode of regulating DNA methylation is through active demethylation driven by TET-mediated oxidation of 5-methylcytosine (5mC). This Review discusses our latest understanding of the mechanisms and regulation of active DNA demethylation, and the roles of active demethylation (and the oxidized 5mC intermediates) in gene regulation, genome stability, development and disease.
- Xiaoji Wu
- Yi Zhang
Review Article30 May 2017 Nature Reviews Genetics
Chromatin dynamics during the cell cycle at centromeres

During the cell cycle, the centromeres of chromosomes have important roles and face key challenges, such as mediating successful chromosome segregation during mitosis and faithfully propagating their chromatin state to daughter chromosomes during S phase. This Review describes cell cycle-related features of centromeres, focusing on the nature and dynamics of centromeric chromatin, how it is intricately regulated and the potential implications for disease when these processes are disrupted.
- Sebastian Müller
- Geneviève Almouzni
Review Article31 Jan 2017 Nature Reviews Genetics
From profiles to function in epigenomics

A wealth of data is emerging from diverse studies of epigenomics, including genome-scale profiles of DNA methylation, histone modifications and higher-order chromatin features. In this Review, the authors discuss how, despite all this information, many challenges remain for inferring and proving the physiological and pathological functions of chromatin states. They describe the degrees of 'functionality' that are revealed by different experimental approaches, the value of integrative strategies and visions for the future.
- Stefan H. Stricker
- Anna Köferle
- Stephan Beck
Review Article21 Nov 2016 Nature Reviews Genetics
Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications

Studies have demonstrated that paternal traits acquired in response to environmental conditions can be inherited by the offspring, sometimes persisting for multiple generations. In this Review, the authors discuss the accumulating evidence of a major role for sperm RNAs and RNA modifications in the inheritance of acquired traits and the mechanisms that may underlie this.
- Qi Chen
- Wei Yan
- Enkui Duan
Review Article3 Oct 2016 Nature Reviews Genetics
Targeting the cancer epigenome for therapy

Recent drug discovery efforts in cancer have focused on epigenetic marks, such as DNA methylation and histone modifications. The authors discuss existing therapeutics that target the cancer epigenome, the role of epigenetic marks as biomarkers of drug response and emerging strategies that combine epigenetic drugs with other cancer therapies.
- Peter A. Jones
- Jean-Pierre J. Issa
- Stephen Baylin
Review Article15 Sep 2016 Nature Reviews Genetics
Transcription factors as readers and effectors of DNA methylation

Evidence is emerging that transcription factors (TFs) lacking methyl-CpG binding domains can interact with methylated DNA. This Analysis article reviews thein vitro and in vivoevidence for methylation-mediated interactions between TFs and DNA, and their functional consequences.
- Heng Zhu
- Guohua Wang
- Jiang Qian
Analysis1 Aug 2016 Nature Reviews Genetics
The molecular hallmarks of epigenetic control

Over the past few decades, epigenetics has evolved from a collection of curious biological phenomena to a functionally dissected research field. In this article, the authors provide a personal perspective on the advances of research into epigenetics — from its historical origins to its modern era — with a focus on molecular breakthroughs.
- C. David Allis
- Thomas Jenuwein
Timeline27 Jun 2016 Nature Reviews Genetics
Genetic sources of population epigenomic variation

The authors review recent studies into the heritable basis of population epigenomic variation and discuss important challenges when interpreting results from these genetic studies in different species to highlight the state of knowledge regarding how genetic variation can influence differences in chromatin states between individuals.
- Aaron Taudt
- Maria Colomé-Tatché
- Frank Johannes
Review Article9 May 2016 Nature Reviews Genetics
Epigenetic modulators, modifiers and mediators in cancer aetiology and progression

Disruption to the epigenome is increasingly appreciated as a major contributor to the development of cancer. The authors discuss how conceptualizing genes affecting the epigenome as epigenetic modulators, epigenetic modifiers or epigenetic mediators provides a valuable framework for understanding diverse aspects of the causes and consequences of epigenome alteration in cancer.
- Andrew P. Feinberg
- Michael A. Koldobskiy
- Anita Göndör
Review Article14 Mar 2016 Nature Reviews Genetics
Single-cell epigenomics: techniques and emerging applications

Various methodologies have been developed to characterize diverse features of chromatin, but understanding how epigenomic states contribute to cellular heterogeneity requires adoption of these techniques at the single-cell level. This article discusses the technological developments driving single-cell epigenomics, including the practical and bioinformatic challenges and emerging biological insights.
- Omer Schwartzman
- Amos Tanay
Review Article13 Oct 2015 Nature Reviews Genetics
Molecular insights into transgenerational non-genetic inheritance of acquired behaviours

In this Review, the authors discuss the concept, and possible mechanisms, of non-genetic transgenerational inheritance. They outline the evidence to date that environmental factors can influence behaviour across generations in mammals through the modification of epigenetic marks and/or non-coding RNAs.
- Johannes Bohacek
- Isabelle M. Mansuy
Review Article29 Sep 2015 Nature Reviews Genetics
Chromatin regulation at the frontier of synthetic biology

Synthetic biology approaches to characterize gene regulation have largely used transcription factor circuits in bacteria. However, the multilayered regulation of genes by chromatin in eukaryotes provides opportunities for more sophisticated control of gene expression. This Review describes diverse approaches for engineering eukaryotic chromatin states, the insights gained into physiological gene regulation principles, and the broad potential applications throughout biomedical research and industry.
- Albert J. Keung
- J. Keith Joung
- James J. Collins
Review Article10 Feb 2015 Nature Reviews Genetics
RNA-mediated epigenetic regulation of gene expression

Small and long non-coding RNAs have emerged as key regulators of gene expression through their direct and indirect actions on chromatin. This Review describes how RNAs form powerful surveillance systems that detect and silence inappropriate transcription events, and how such systems provide a memory of these events via self-reinforcing epigenetic loops.
- Daniel Holoch
- Danesh Moazed
Review Article2 Jan 2015 Nature Reviews Genetics
High-resolution digital profiling of the epigenome

The resolution of epigenomic profiling has been vastly augmented with the adoption of new approaches to interrogate varied features of the epigenome. This Review describes these techniques and outlines the ways in which these genome-wide tools can be used to examine the epigenome.
- Gabriel E. Zentner
- Steven Henikoff
Review Article9 Oct 2014 Nature Reviews Genetics
Identifying and mitigating bias in next-generation sequencing methods for chromatin biology

Next-generation sequencing methods can be used to examine features of chromatin biology, although the outputs of these methods can be subject to various potential biases. This Review describes the ways in which biases can be introduced to such experiments and outlines methods to detect and mitigate their effect.
- Clifford A. Meyer
- X. Shirley Liu
Review Article16 Sep 2014 Nature Reviews Genetics
Eusocial insects as emerging models for behavioural epigenetics

This Review provides insights into the use of eusocial insect species as models to study the role of epigenetic processes in regulating behaviour.
- Hua Yan
- Daniel F. Simola
- Danny Reinberg
Review Article9 Sep 2014 Nature Reviews Genetics
Advances in the profiling of DNA modifications: cytosine methylation and beyond

Recent developments and refinements to DNA methylation assays have led to the availability of several methods to detect and quantify cytosine modifications. This Review discusses the principles behind the newly developed techniques, compares the strengths and weaknesses of the different methods, and provides guidelines for selecting the most appropriate methods for particular experimental contexts.
- Nongluk Plongthongkum
- Dinh H. Diep
- Kun Zhang
Review Article27 Aug 2014 Nature Reviews Genetics
Epigenetic reprogramming in plant sexual reproduction

DNA and histone modifications undergo extensive reprogramming to reset the epigenomic state between generations. This Review discusses the mechanisms and consequences of epigenetic reprogramming during plant sexual reproduction. Despite various similarities to the equivalent process in mammals, a key difference is the seemingly incomplete reprogramming of plant epigenomes, which has implications for evolution and transgenerational epigenetic inheritance.
- Tomokazu Kawashima
- Frédéric Berger
Review Article22 Jul 2014 Nature Reviews Genetics
The role of genomic imprinting in biology and disease: an expanding view

Imprinted genes influence a wide range of biological processes, the effects of which extend from prenatal stages to adulthood. This Review discusses the role of imprinted genes, with a focus on postnatal and adult phenotypes, and their contribution to common diseases such as intrauterine growth restriction, obesity, psychiatric disorders and cancer.
- Jo Peters
Review Article24 Jun 2014 Nature Reviews Genetics
RNA-directed DNA methylation: an epigenetic pathway of increasing complexity

RNA-directed DNA methylation (RdDM) is a major mechanism of transcriptional gene silencing in plants that is mediated through small interfering RNAs (siRNAs) and plant-specific RNA polymerases. This Review summarizes our latest understanding of RdDM, including its genomic targets, molecular mechanisms (such as emerging non-canonical pathways) and diverse biological roles.
- Marjori A. Matzke
- Rebecca A. Mosher
Review Article8 May 2014 Nature Reviews Genetics
Every amino acid matters: essential contributions of histone variants to mammalian development and disease

Increasing evidence suggests crucial functions for histone variants in diverse biological processes. This Review examines the roles of histone variants in mammalian germ cell and embryonic development, as well as the consequences of their aberrant regulation in human disease.
- Ian Maze
- Kyung-Min Noh
- C. David Allis
Review Article11 Mar 2014 Nature Reviews Genetics
Chromatin modifiers and remodellers: regulators of cellular differentiation

This Review describes the diverse roles for histone-modifying and chromatin-remodelling enzymes in mammalian differentiation. These enzymes are involved in both maintaining pluripotency and specifying cell lineage commitment. Recent progress includes their functional characterization in mouse modelsin vivoand a new appreciation of their multifaceted molecular functions.
- Taiping Chen
- Sharon Y. R. Dent
Review Article24 Dec 2013 Nature Reviews Genetics
A new world of Polycombs: unexpected partnerships and emerging functions

Polycomb group (PcG) proteins have long been known to have repressive functions. Recently, novel complexes of PcG proteins have been identified and have been shown to have novel molecular and biological functions, which are discussed in this Review.
- Yuri B. Schwartz
- Vincenzo Pirrotta
Review Article12 Nov 2013 Nature Reviews Genetics
Mutations in regulators of the epigenome and their connections to global chromatin patterns in cancer

There is an increasing realization of epigenetic dysregulation in cancer, which comprises both the mutation of genes encoding epigenetic regulators and the broader disruptions to chromatin states of the epigenome. This Review discusses our latest understanding of these phenomena, their convergence and the implications for cancer biology and therapeutics.
- Christoph Plass
- Stefan M. Pfister
- Peter Lichter
Review Article9 Oct 2013 Nature Reviews Genetics

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