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Epigenome
Epigenome
Epigenome
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The function of DNA strands (yellow) alters depending on how it is organized around histones (blue) that can be methylated (green).

In biology, the epigenome of an organism is the collection of chemical changes to its DNA and histone proteins that affects when, where, and how the DNA is expressed; these changes can be passed down to an organism's offspring via transgenerational epigenetic inheritance. Changes to the epigenome can result in changes to the structure of chromatin and changes to the function of the genome.[1] The human epigenome, including DNA methylation and histone modification, is maintained through cell division (both mitosis and meiosis).[2] The epigenome is essential for normal development and cellular differentiation, enabling cells with the same genetic code to perform different functions. The human epigenome is dynamic and can be influenced by environmental factors such as diet, stress, and toxins.

The epigenome is involved in regulating gene expression, development, tissue differentiation, and suppression of transposable elements. Unlike the underlying genome, which remains largely static within an individual, the epigenome can be dynamically altered by environmental conditions.

Types

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Main article: Epigenetics

The main types of epigenetic changes include:[3]

DNA methylation

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Main article: DNA methylation

Addition of a methyl group to the DNA molecule, typically at cytosine bases. This modification generally leads to gene silencing by preventing the binding of transcription factors and other proteins necessary for gene expression.[3]

DNA functionally interacts with a variety of epigenetic marks, such as cytosine methylation, also known as 5-methylcytosine (5mC). This epigenetic mark is widely conserved and plays major roles in the regulation of gene expression, in the silencing of transposable elements and repeat sequences.[4]

Individuals differ with their epigenetic profile, for example the variance in CpG methylation among individuals is about 42%. On the contrary, epigenetic profile (including methylation profile) of each individual is constant over the course of a year, reflecting the constancy of our phenotype and metabolic traits. Methylation profile, in particular, is quite stable in a 12-month period and appears to change more over decades.[5]

Methylation sites

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CoRSIVs are Correlated Regions of Systemic Interindividual Variation in DNA methylation. They span only 0.1% of the human genome, so they are very rare; they can be inter-correlated over long genomic distances (>50 kbp). CoRSIVs are also associated with genes involved in a lot of human disorders, including tumors, mental disorders and cardiovascular diseases. It has been observed that disease-associated CpG sites are 37% enriched in CoRSIVs compared to control regions and 53% enriched in CoRSIVs relative to tDMRs (tissue specific Differentially Methylated Regions).[6]

Most of the CoRSIVs are only 200 – 300 bp long and include 5–10 CpG dinucleotides, the largest span several kb and involve hundreds of CpGs. These regions tend to occur in clusters and the two genomic areas of high CoRSIV density are observed at the major histocompatibility (MHC) locus on chromosome 6 and at the pericentromeric region on the long arm of chromosome 20.[6]

CoRSIVs are enriched in intergenic and quiescent regions (e.g. subtelomeric regions) and contain many transposable elements, but few CpG islands (CGI) and transcription factor binding sites. CoRSIVs are under-represented in the proximity of genes, in heterochromatic regions, active promoters, and enhancers. They are also usually not present in highly conserved genomic regions.[6]

CoRSIVs can have a useful application: measurements of CoRSIV methylation in one tissue can provide some information about epigenetic regulation in other tissues, indeed we can predict the expression of associated genes because systemic epigenetic variants are generally consistent in all tissues and cell types.[7]

Factors affecting methylation pattern

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Quantification of the heritable basis underlying population epigenomic variation is also important to delineate its cis- and trans-regulatory architecture. In particular, most studies state that inter-individual differences in DNA methylation are mainly determined by cis-regulatory sequence polymorphisms, probably involving mutations in TFBSs (Transcription Factor Binding Sites) with downstream consequences on local chromatin environment. The sparsity of trans-acting polymorphisms in humans suggests that such effects are highly deleterious. Indeed, trans-acting factors are expected to be caused by mutations in chromatin control genes or other highly pleiotropic regulators. If trans-acting variants do exist in human populations, they probably segregate as rare alleles or originate from somatic mutations and present with clinical phenotypes, as is the case in many cancers.[4]

Correlation between methylation and gene expression

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DNA methylation (in particular in CpG regions) is able to affect gene expression: hypermethylated regions tend to be differentially expressed. In fact, people with a similar methylation profile tend to also have the same transcriptome. Moreover, one key observation from human methylation is that most functionally relevant changes in CpG methylation occur in regulatory elements, such as enhancers.

Anyway, differential expression concerns only a slight number of methylated genes: only one fifth of genes with CpG methylation shows variable expression according to their methylation state. It is important to notice that methylation is not the only factor affecting gene regulation.[5]

Methylation in embryos

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It was revealed by immunostaining experiments that in human preimplantation embryos there is a global DNA demethylation process. After fertilisation, the DNA methylation level decreases sharply in the early pronuclei. This is a consequence of active DNA demethylation at this stage. But global demethylation is not an irreversible process, in fact de novo methylation occurring from the early to mid-pronuclear stage and from the 4-cell to the 8-cell stage.[8]

The percentage of DNA methylation is different in oocytes and in sperm: the mature oocyte has an intermediate level of DNA methylation (72%), instead the sperm has high level of DNA methylation (86%). Demethylation in paternal genome occurs quickly after fertilisation, whereas the maternal genome is quite resistant at the demethylation process at this stage. Maternal different methylated regions (DMRs) are more resistant to the preimplantation demethylation wave.[8]

CpG methylation is similar in germinal vesicle (GV) stage, intermediate metaphase I (MI) stage and mature metaphase II (MII) stage. Non-CpG methylation continues to accumulate in these stages.[8]

Chromatin accessibility in germline was evaluated by different approaches, like scATAC-seq and sciATAC-seq, scCOOL-seq, scNOMe-seq and scDNase-seq. Stage-specific proximal and distal regions with accessible chromatin regions were identified. Global chromatin accessibility is found to gradually decrease from the zygote to the 8-cell stage and then increase. Parental allele-specific analysis shows that paternal genome becomes more open than the maternal genome from the late zygote stage to the 4-cell stage, which may reflect decondensation of the paternal genome with replacement of protamines by histones.[8]

Sequence-Dependent Allele-Specific Methylation

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DNA methylation imbalances between homologous chromosomes show sequence-dependent behavior. Difference in the methylation state of neighboring cytosines on the same chromosome occurs due to the difference in DNA sequence between the chromosomes. Whole-genome bisulfite sequencing (WGBS) is used to explore sequence-dependent allele-specific methylation (SD-ASM) at a single-chromosome resolution level and comprehensive whole-genome coverage. The results of WGBS tested on 49 methylomes revealed CpG methylation imbalances exceeding 30% differences in 5% of the loci.[9]

On the sites of gene regulatory loci bound by transcription factors the random switching between methylated and unmethylated states of DNA was observed. This is also referred as stochastic switching and it is linked to selective buffering of gene regulatory circuit against mutations and genetic diseases. Only rare genetic variants show the stochastic type of gene regulation.

The study made by Onuchic et al. was aimed to construct the maps of allelic imbalances in DNA methylation, gene transcription, and also of histone modifications. 36 cell and tissue types from 13 participant donors were used to examine 71 epigenomes. The results of WGBS tested on 49 methylomes revealed CpG methylation imbalances exceeding 30% differences in 5% of the loci. The stochastic switching occurred at thousands of heterozygous regulatory loci that were bound to transcription factors. The intermediate methylation state is referred to the relative frequencies between methylated and unmethylated epialleles. The epiallele frequency variations are correlated with the allele affinity for transcription factors.

The analysis of the study suggests that human epigenome in average covers approximately 200 adverse SD-ASM variants. The sensitivity of the genes with tissue-specific expression patterns gives the opportunity for the evolutionary innovation in gene regulation.[9]

Haplotype reconstruction strategy is used to trace chromatin chemical modifications (using ChIP-seq) in a variety of human tissues. Haplotype-resolved epigenomic maps can trace allelic biases in chromatin configuration. A substantial variation among different tissues and individuals is observed. This allows the deeper understanding of cis-regulatory relationships between genes and control sequences.[10]

Histone modification

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Main article: Histone modification

Post-translational modifications of histone proteins, which include methylation, acetylation, phosphorylation, ubiquitination, and sumoylation. These modifications can either activate or repress gene expression by altering chromatin structure and accessibility of the DNA to transcriptional machinery.

The epigenetic profiles of human tissues reveals the following distinct histone modifications in different functional areas:[10]

Active Promoters Active Enhancers Transcribed Gene Bodies Silenced Regions
H3K4me3 H3K4me1 H3K36me3 H3K27me3
H3K27ac H3K27ac H3K9me3

Acetylation

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Main article: Histone acetylation

Histone acetylation neutralizes the positive charge on histones. This weakens the electrostatic attraction to negatively charged DNA and causes unwinding of DNA from histones, making the DNA more accessible to the transcriptional machinery and hence resulting in transcriptional activation.[11]

Methylation

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Main article: Histone methylation

Can lead to activation or repression of gene expression depending on the specific amino acids that are methylated.

Non-coding RNA gene silencing

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Non-coding RNA (ncRNA) gene silencing involves various types of non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and small interfering RNAs (siRNAs). These RNA molecules can modulate gene expression by various mechanisms, including mRNA degradation, inhibition of translation, and chromatin remodeling.[3]

Structural modifications

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During the last few years, several methods have been developed to study the structural and consequently the functional modifications of chromatin. The first project that used epigenomic profiling to identify regulatory elements in the human genome was ENCODE (Encyclopedia of DNA Elements) that focused on profiling histone modifications on cell lines. A few years later ENCODE was included in the International Human Epigenome Consortium (IHEC), which aims to coordinate international epigenome studies.[12]

The structural modifications that these projects aim to study can be divided into five main groups:

  • Nucleosome occupancy to detect regions with regulatory genes;
  • Chromatin interactions and domains;[12]

Topological associated domains (TADs)

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Topological associated domains are a degree of structural organization of the genome of the cell. They are formed by regions of chromatin, sized from 100 kilobases up to megabases, which highly self-interact. The domains are linked by other genomic regions, which, based on their size, are either called “topological boundary regions” or “unorganized chromatin”. These boundary regions separate the topological domains from heterochromatin, and prevent the amplification of the latter. Topological domains are diffused in mammalian, although similar genome partitions were identified also in Drosophila.[13]

Topological domains in humans, like in other mammalians, have many functions regarding gene expression and transcriptional control process. Inside these domains, the chromatin shows to be well tangled, while in the boundary regions chromatin interactions are far less present.[14] These boundary areas in particular show some peculiarity that determine the functions of all the topological domains.

Firstly, they contain insulator regions and barrier elements, both of which function as inhibitors of further transcription from the RNA polymerase enzyme.[15] Such elements are characterized by the massive presence of insulator binding proteins CTCF.

Secondly, boundary regions block heterochromatin spreading, thus preventing the loss of useful genetic informations. This information derives from the observation that the heterochromatin mark H3K9me3 sequences clearly interrupts near boundary sequences.[16]

Thirdly, transcription start sites (TSS), housekeeping genes and tRNA genes are particularly abundant in boundary regions, denoting that those areas have a prolific transcriptional activity, thanks to their structural characteristics, different from other topological regions.[17][18]

Finally, in the border areas of the topological domains and their surroundings there is an enrichment of Alu/B1 and B2 SINE retrotransposons. In the recent years, those sequences were referred to alter binding site of CTCF, thus interfering with expression of some genomic areas.[19]

Further proofs towards a role in genetic modulation and transcription regulation refers to the great conservation of the boundary pattern across mammalian evolution, with a dynamic range of small diversities inside different cell types, suggesting that these topological domains take part in cell-type specific regulatory events.[14]

Correlation between methylation and 3D structure

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The 4D Nucleome project aims to realize a 3D maps of mammalian genomes in order to develop predictive models to correlate epigenomic modifications with genetic variation. In particular the goal is to link genetic and epigenomic modifications with the enhancers and promoters which they interact with in three-dimensional space, thus discovering gene-set interactomes and pathways as new candidates for functional analysis and therapeutic targeting.

Hi-C [20] is an experimental method used to map the connections between DNA fragments in three-dimensional space on a genome-wide scale. This technique combines chemical crosslinking of chromatin with restriction enzyme digestion and next-generation DNA sequencing.[21]

This kind of studies are currently limited by the lack or unavailability of raw data.[12]

Clinical significance

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Cancer

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Epigenetics is a currently active topic in cancer research. Human tumors undergo a major disruption of DNA methylation and histone modification patterns. The aberrant epigenetic landscape of the cancer cell is characterized by a global genomic hypomethylation, CpG island promoter hypermethylation of tumor suppressor genes, an altered histone code for critical genes and a global loss of monoacetylated and trimethylated histone H4.

Aging

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The idea that DNA damage drives aging by compromising transcription and DNA replication has been widely supported since it was initially developed the 1980s.[22] In recent decades, evidence has accumulated supporting the additional idea that DNA damage and repair elicit widespread epigenome alterations that also contribute to aging (e.g.[23][24]). Such epigenome changes include age-related changes in the patterns of DNA methylation and histone modification.[23]

Research

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As a prelude to a potential Human Epigenome Project, the Human Epigenome Pilot Project aims to identify and catalogue Methylation Variable Positions (MVPs) in the human genome.[25] Advances in sequencing technology now allow for assaying genome-wide epigenomic states by multiple molecular methodologies.[26] Micro- and nanoscale devices have been constructed or proposed to investigate the epigenome.[27]

An international effort to assay reference epigenomes commenced in 2010 in the form of the International Human Epigenome Consortium (IHEC).[28][29][30][31] IHEC members aim to generate at least 1,000 reference (baseline) human epigenomes from different types of normal and disease-related human cell types.[32][33][34]

Roadmap epigenomics project

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One goal of the NIH Roadmap Epigenomics Project Archived 2021-04-08 at the Wayback Machine is to generate human reference epigenomes from normal, healthy individuals across a large variety of cell lines, primary cells, and primary tissues. Data produced by the project, which can be browsed and downloaded from the Human Epigenome Atlas, fall into five types that assay different aspects of the epigenome and outcomes of epigenomic states (such as gene expression):

  1. Histone Modifications – Chromatin Immunoprecipitation Sequencing (ChIP-Seq) identifies genome wide patterns of histone modifications using antibodies against the modifications.[35]
  2. DNA Methylation – Whole Genome Bisulfite-Seq, Reduced Representation Bisulfite-Seq (RRBS), Methylated DNA Immunoprecipitation Sequencing (MeDIP-Seq), and Methylation-sensitive Restriction Enzyme Sequencing (MRE-Seq) identify DNA methylation across portions of the genome at varying levels of resolution down to basepair level.[36]
  3. Chromatin Accessibility – DNase I hypersensitive sites Sequencing (DNase-Seq) uses the DNase I enzyme to find open or accessible regions in the genome.
  4. Gene Expression – RNA-Seq and expression arrays identify expression levels or protein coding genes.
  5. Small RNA Expression – smRNA-Seq identifies expression of small noncoding RNA, primarily miRNAs.

Reference epigenomes for healthy individuals will enable the second goal of the Roadmap Epigenomics Project, which is to examine epigenomic differences that occur in disease states such as Alzheimer's disease.

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Epigenome

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The epigenome encompasses the complete array of chemical modifications to DNA and associated proteins, such as histones, that influence gene expression without changing the underlying DNA sequence in a specific cell type or organism. These modifications form a dynamic layer of regulation that directs cellular identity, development, and response to environmental cues, ensuring that genes are activated or silenced appropriately across diverse tissues and life stages. The primary components of the epigenome include , where methyl groups are added to bases, typically repressing transcription; histone modifications, such as , , and , which alter structure to either promote or inhibit access to genetic information; and non-coding RNAs that guide these processes. Additional elements, like and imprinting, contribute to the epigenome's complexity, enabling heritable yet reversible control over genomic function during and differentiation. This system is cell-type specific, meaning the epigenome varies widely between, for example, neurons and liver cells, despite their shared . The epigenome plays a pivotal role in biological processes, including embryonic development, where it orchestrates the precise timing of activation for tissue formation; aging, through progressive accumulation of marks that affect ; and adaptation to external factors like diet, stress, or toxins, which can induce lasting changes. Dysregulation of the epigenome is implicated in numerous diseases, such as cancer, where aberrant silences tumor suppressor , and neurological disorders, highlighting its therapeutic potential through targeted drugs like HDAC inhibitors. Ongoing research, including large-scale epigenome mapping projects, continues to uncover how environmental influences shape this regulatory landscape, offering insights into and preventive strategies.

Fundamentals

Definition and Overview

The epigenome comprises the complete set of chemical modifications and structural configurations overlying the that influence without altering the underlying DNA sequence. These modifications include , histone variants and modifications, and complexes, which collectively form a dynamic regulatory layer specific to individual cell types or physiological conditions. This framework enables precise control over which genes are activated or silenced in response to developmental cues or external signals, ensuring cellular identity and function across diverse tissues. The concept of the epigenome builds on the foundational idea of , first articulated by Conrad Waddington in as the study of interactions between genes and their environment during development. The term "epigenome" itself emerged in the late 1990s, coinciding with the launch of the Human Epigenome Project in 1999, which aimed to map these modifications genome-wide to understand their role in health and disease. This evolution reflected advances in that highlighted how epigenetic marks extend Waddington's vision to a holistic, heritable beyond the static . Key features of the epigenome include its cell-type specificity, reversibility, and sensitivity to environmental influences such as diet, stress, or toxins. For instance, while all cells in an organism share the same DNA sequence, the epigenome in liver cells prioritizes metabolic gene expression through distinct methylation patterns, whereas in neurons it favors synaptic and neural signaling pathways, enabling specialized functions despite genomic identity. These properties allow the epigenome to adapt dynamically, maintaining stability during cell division while permitting reprogramming in response to stimuli.

Relation to Genome

The genome refers to the complete set of an organism's DNA sequence, which remains fixed throughout life and serves as the blueprint for genetic information. In contrast, the epigenome comprises dynamic chemical modifications to DNA and associated proteins, such as histones, that regulate gene expression without altering the underlying DNA sequence itself. These modifications act as an additional layer of control, determining which genes are activated or silenced in specific cells or tissues, thereby enabling functional diversity from a single genetic template. This relationship can be conceptualized as a layered model, where the epigenome functions as an "epigenetic code" that overlays the . The epigenetic code influences transcription by modulating structure—compacting it into inaccessible to repress genes or loosening it into to promote expression—without requiring changes to the nucleotide sequence. Unlike the uniform present across all cells, the epigenetic code exhibits cell-type specificity, allowing a to develop diverse phenotypes from identical genomic material. A useful for this interface is that of hardware and software: the provides the stable hardware (DNA sequence), while the epigenome supplies the software instructions that dictate how that hardware is utilized for and cellular function. Evidence for this distinction comes from studies of monozygotic twins, who share identical but accumulate epigenetic differences over time due to environmental and lifestyle factors. For instance, older twin pairs show marked variations in and acetylation patterns, correlating with divergent profiles and phenotypic traits, such as increased disease susceptibility in one twin over the other.

Inheritance and Stability

The stability of the epigenome during is primarily achieved through mitotic maintenance mechanisms that preserve epigenetic marks across generations of daughter cells. During in , the maintenance copies patterns from the parental strand to the newly synthesized daughter strand, ensuring the propagation of states. This process is facilitated by the recruitment of to hemimethylated DNA via the protein UHRF1, which recognizes hemimethylated CpG sites and directs activity, thereby safeguarding epigenetic information against dilution during proliferation. In addition, alternative recruitment modes, such as ubiquitin-mediated interactions involving (PCNA) and monoubiquitinated PAF15, support loading particularly at early-replicating genomic regions, contributing to the overall fidelity of . These mechanisms collectively maintain epigenetic stability in somatic cells, preventing loss that could disrupt gene regulation. While mitotic inheritance is robust within an organism's lifetime, meiotic transmission of epigenetic states across generations—known as transgenerational epigenetics—is more constrained in animals but well-documented in . In plants, paramutation exemplifies this process, where one induces a heritable epigenetic change in a homologous , leading to stable, meiotically transmitted alterations in , as observed in loci like b1 and pl1. In mammals, evidence for transgenerational inheritance is rarer due to extensive , but cases exist, such as RNA-mediated paramutation at the Kit locus in mice, where microRNAs from a silence the wild-type in , resulting in heritable white tail spotting phenotypes transmitted through multiple generations. Similarly, induced changes at promoter-associated CpG islands can be memorized and passed from parents to in mice, bypassing typical erasure. These examples highlight how exceptions to enable limited in mammals, potentially adapting to environmental pressures. Epigenetic stability is periodically reset through erasure and events, particularly in the and early , to restore developmental plasticity. In mammalian preimplantation embryos, global occurs via active demethylation mediated by TET3 and replication-dependent dilution, erasing most gametic patterns by the stage. However, exceptions persist for imprinted genes, where differentially methylated regions (DMRs) resist erasure through protective mechanisms like Stella/PGC7 binding, which shields maternal imprints from TET3 activity, ensuring parent-of-origin-specific expression in . This selective preservation balances the need for epigenetic renewal with the maintenance of essential monoallelic regulation. Environmental factors can influence epigenetic stability, inducing heritable changes that persist across generations. For instance, prenatal exposure to the Dutch Hunger Winter famine (1944–1945) in the led to altered signatures in survivors, particularly at growth-related genes like IGF2, with effects detectable decades later and even in their offspring, suggesting transgenerational transmission of metabolic risk. Such exposures demonstrate how acute nutritional stress can reprogram the epigenome in a way that evades complete erasure, contributing to intergenerational outcomes.

Epigenetic Modifications

DNA Methylation

DNA methylation is a key epigenetic modification involving the covalent addition of a methyl group to the fifth carbon of cytosine bases, primarily within CpG dinucleotides, to form 5-methylcytosine (5mC). This process is catalyzed by DNA methyltransferases (DNMTs), with DNMT3A and DNMT3B responsible for de novo methylation of previously unmethylated DNA during development, and DNMT1 maintaining methylation patterns across cell divisions by recognizing hemimethylated DNA post-replication. In mammals, approximately 70-80% of CpG sites are methylated genome-wide, contributing to stable gene regulation without altering the underlying DNA sequence. Methylation predominantly occurs at promoter regions associated with CpG islands (CGIs), gene bodies, and enhancers, where patterns influence accessibility and transcriptional output. Promoter often targets CGIs, which are CpG-rich sequences typically unmethylated in active , while gene body is common in highly expressed and may prevent spurious transcription initiation. Enhancers exhibit dynamic , with hypomethylation marking active regulatory elements and facilitating binding; global hypomethylation is observed in transcriptionally active regions, contrasting with hypermethylation in repressed areas. DNA methylation patterns are shaped by intrinsic factors like age and sequence context, as well as extrinsic environmental influences. With aging, CpG island-associated loci tend to gain , while non-island CpG sites lose it, leading to tissue-specific alterations detectable across hundreds of loci. Environmental exposures, such as smoking, induce dose-dependent changes, including hypomethylation at over 100 CpG sites in lung tissue and altered in blood genes like AHRR and MLH1, reflecting cumulative exposure effects. Sequence features like CpG density in islands confer resistance to , maintaining low levels to support expression. Hypermethylation at promoters generally represses by inhibiting binding to DNA or recruiting repressive complexes, such as methyl-CpG-binding domain (MBD) proteins and the NuRD complex, which compact . Conversely, hypomethylation promotes activation by enhancing accessibility for activators and reducing repressive marks, particularly at enhancers and low-density CpG regions. These inverse correlations are evident in developmental contexts, where dynamics fine-tune expression levels without permanent sequence changes. An additional layer of DNA modification involves (5hmC), formed by oxidation of 5mC by ten-eleven translocation (TET) enzymes. Unlike 5mC, 5hmC is associated with transcriptional activation and is enriched in bodies of expressed genes, enhancers, and neuronal genomes. It serves as a stable epigenetic mark influencing demethylation pathways, development, and disease states such as cancer and neurodegeneration, with levels varying by tissue and age. Special cases include , where allele-specific ensures parent-of-origin-dependent expression, as seen in the IGF2 gene, whose paternal allele is methylated at the H19 imprinting control region to silence the maternal copy and promote production. Allele-specific can also arise from sequence variants influencing DNMT targeting, independent of imprinting, affecting hundreds of autosomal loci across tissues. During embryonic development, DNA methylation undergoes dynamic waves post-fertilization: rapid global demethylation occurs within hours, primarily affecting the paternal through active and passive mechanisms, followed by de novo remethylation starting at the 4- to 8-cell stage, targeting repeats and imprinted regions. This reprogramming establishes tissue-specific patterns by the stage, with maternal persisting longer. plays a crucial role in X-chromosome inactivation (XCI) in female embryos, stabilizing silencing post-implantation via hyper of promoters on the inactive , initiated by RNA but reinforced by DNMTs.

Histone Modifications

Histones are core proteins that package DNA into nucleosomes, the fundamental units of chromatin. Each nucleosome consists of an octamer formed by two molecules each of histones H2A, H2B, H3, and H4, around which approximately 147 base pairs of DNA are wrapped in about 1.65 left-handed superhelical turns. The N-terminal tails of these histones protrude from the octamer and are subject to post-translational modifications (PTMs) that regulate chromatin structure and function. These modifications are catalyzed by specific enzymes, such as histone acetyltransferases (HATs), which add acetyl groups, and histone deacetylases (HDACs), which remove them, thereby influencing gene expression without altering the DNA sequence. Acetylation is one of the most studied histone PTMs, involving the addition of acetyl groups to the ε-amino group of residues, primarily on tails. This modification neutralizes the positive charge of , reducing the affinity between and negatively charged DNA, which loosens structure and promotes transcriptional activation. For instance, acetylation at 9 (H3K9ac) is associated with open and active transcription, often found at promoters of expressed . HATs, such as p300/CBP, deposit these marks, while HDACs reverse them to restore compact and repress transcription. Methylation involves the addition of one to three methyl groups to lysine or arginine residues and can either activate or repress gene expression depending on the site and degree of methylation. Activating marks like trimethylation of H3 at lysine 4 (H3K4me3) are enriched at active promoters, recruiting transcription factors and RNA polymerase II to facilitate gene expression. In contrast, repressive marks such as trimethylation of H3 at lysine 27 (H3K27me3) promote chromatin condensation and gene silencing, particularly in developmental contexts. The concept of a "histone code," proposed by Jenuwein and Allis, posits that the combinatorial patterns of these modifications on histone tails serve as a dynamic language that specifies distinct chromatin states and epigenetic outcomes. Other PTMs include , which adds phosphate groups to serine, , or residues and is often linked to during processes like , and ubiquitination, the attachment of to residues, which can signal either or repression depending on context. These marks, along with and , form combinatorial patterns that define active or repressed domains. The specificity of these PTMs is governed by "writers" (enzymes that add marks), "erasers" (enzymes that remove them), and "readers" (proteins that recognize them). For example, , a methyltransferase in the Polycomb repressive complex 2 (PRC2), catalyzes as a repressive writer, while bromodomain-containing proteins, such as , act as readers of acetylated s to recruit transcriptional machinery. Erasers like lysine demethylases (e.g., KDMs) ensure reversibility, allowing dynamic regulation of the epigenome.

Non-Coding RNA Mechanisms

Non-coding RNAs (ncRNAs) play crucial roles in epigenetic regulation by guiding chromatin-modifying complexes to specific genomic loci, thereby influencing gene silencing and activation without altering the DNA sequence. Key classes include long non-coding RNAs (lncRNAs, typically >200 nucleotides), microRNAs (miRNAs, ~21-25 nucleotides), and Piwi-interacting RNAs (piRNAs, ~24-31 nucleotides). These RNAs mediate epigenetic effects through direct interactions with proteins or chromatin, often recruiting enzymatic complexes that deposit repressive or activating marks. In gene silencing pathways, lncRNAs such as exemplify RNA-mediated epigenetic repression by coating the in female mammals, which recruits the Polycomb Repressive Complex 2 (PRC2) to deposit trimethylation on lysine 27 (), leading to facultative formation and dosage compensation. Similarly, the lncRNA HOTAIR, overexpressed in various cancers, interacts with PRC2 to target clusters, promoting and facilitating in cells. piRNAs contribute to silencing in the by forming complexes with proteins, which guide the RNA-induced transcriptional silencing (RITS)-like machinery to transposon loci, preventing their mobilization and maintaining genomic integrity through formation. miRNAs, while primarily acting post-transcriptionally by binding mRNA to induce degradation or translational repression, also influence indirectly by targeting transcripts of epigenetic regulators like DNA methyltransferases (DNMTs) or histone deacetylases (HDACs), thereby derepressing or enhancing silencing of target genes. ncRNAs enable precise by serving as scaffolds or guides for modifiers. For instance, lncRNAs can tether PRC2 or other complexes to promoter regions via sequence-specific interactions, as seen with HOTAIR's recruitment to polycomb-responsive elements. piRNAs exemplify this in transposon control, where primary piRNAs derived from transposon clusters initiate a ping-pong amplification cycle with secondary piRNAs, directing to nascent transcripts for slicing and subsequent assembly in cells. These mechanisms often intersect with modifications, where ncRNAs enhance the specificity of enzymatic deposition. Beyond repression, certain lncRNAs promote gene activation by facilitating chromatin looping between enhancers and promoters. For example, the lncRNA HOTTIP interacts with the WDR5/MLL complex at the 5' Hox locus, stabilizing three-dimensional contacts that activate HOXA genes during limb development. This looping mechanism allows distant regulatory elements to converge, boosting transcriptional output in a tissue-specific manner.

Chromatin Organization

Topological Associated Domains

Topologically associating domains (TADs) are self-interacting regions of that represent fundamental units of higher-order organization in eukaryotic cells. These domains are characterized by frequent physical interactions among DNA sequences within the same TAD, while interactions between sequences in adjacent TADs are significantly reduced. TADs were first identified in the early 2010s through high-throughput interaction mapping techniques, revealing them as pervasive features of mammalian s in both embryonic stem cells and differentiated cell types. The formation of TADs is primarily driven by the loop extrusion model, in which ring-shaped protein complexes such as actively extrude loops until they are halted by convergent binding sites of the insulator protein at domain boundaries. , loaded onto by the loader protein Nipbl, forms dynamic loops that grow progressively larger, promoting intra-domain contacts, while CTCF-bound sites act as barriers to prevent extrusion across boundaries, thereby defining the spatial confines of each TAD. This mechanism ensures the compartmentalization of regulatory elements and genes within discrete territories. TADs typically span 100 kilobases (kb) to 1 megabase (Mb) in size, with a median length of approximately 700-1000 kb, and number in the thousands per haploid —around 2500-3000 in cells. These domains are largely conserved in position and structure across different cell types within a species and even between closely related species like and , though subtle shifts in boundary positions can occur during development or in response to cellular states. Functionally, TADs serve to insulate enhancers from acting on non-target in adjacent domains, thereby restricting regulatory interactions and preventing ectopic or misregulation. Disruptions to TAD boundaries, such as through deletions or inversions, can merge adjacent domains, leading to aberrant enhancer-promoter contacts and diseases; for instance, structural variants at the EPHA4 locus that abolish TAD insulation cause congenital limb malformations in humans by allowing limb-specific enhancers to inappropriately activate neighboring . TADs are detected using variants of (3C) technologies, which quantify pairwise interactions genome-wide. The foundational 3C method involves crosslinking of interacting regions, followed by digestion, ligation of proximal fragments, and PCR amplification to identify ligation products. High-throughput extensions like incorporate deep sequencing to generate comprehensive interaction maps at kilobase resolution, enabling the computational identification of TADs as regions of elevated intra-domain contact frequency. Other derivatives, such as 4C and 5C, provide higher resolution for targeted or array-based analyses but are less commonly used for genome-wide TAD calling compared to .

Integration with Epigenetic Marks

Epigenetic modifications and chromatin's three-dimensional (3D) structure exhibit bidirectional interactions, where histone marks and DNA methylation patterns both shape and are shaped by higher-order chromatin folding. Active histone modifications, such as trimethylation of lysine 4 on histone H3 (H3K4me3), are strongly correlated with open A compartments—regions characterized by high gene activity and self-associating interactions—as well as enhancer-promoter looping that facilitates transcriptional activation. In contrast, repressive marks like trimethylation of lysine 27 on histone H3 (H3K27me3) predominate in closed B compartments, which are associated with gene silencing and heterochromatin compaction, thereby restricting inter-domain contacts. These associations underscore how epigenetic states dictate compartmentalization, while structural rearrangements can propagate mark deposition through mechanisms like Polycomb group protein spreading. DNA methylation further modulates chromatin folding by influencing topological associated domain (TAD) insulation at boundaries. Hypomethylation at -binding sites within TAD boundaries promotes occupancy, enhancing loop extrusion barriers and strengthening insulation to prevent ectopic enhancer-promoter interactions across domains. Conversely, hypermethylation at these sites disrupts binding, weakening boundary insulation and permitting aberrant contacts that can alter regulation. This dynamic is evident in contexts like pericentromeric regions, where elevated methylation promotes condensation and intra-domain compaction, reinforcing compartmental separation. During , shifts in epigenetic marks drive remodeling of TAD boundaries and overall architecture, particularly in stem cells transitioning to committed lineages. For instance, in human embryonic stem cells, pluripotency-associated mark changes, such as reduced at specific loci, coincide with TAD boundary strengthening and compartment switching, enabling lineage-specific . These alterations facilitate the establishment of stable 3D configurations that lock in cellular identity, with models illustrating how multivalent histone modifications, like H3K27me3 recruitment by Polycomb proteins, condense repressive domains into liquid-like condensates. Recent studies (2024–2025) have further highlighted 3D folding, including TADs, as an emerging epigenetic mechanism for stabilizing transcriptional states during development and in contexts. Disruption of TADs provides compelling evidence for this integration, as structural breaks often lead to secondary changes in patterns and enhancer hijacking, a hallmark of oncogenesis. In cancer genomes, TAD boundary deletions or inversions can relocate enhancers into neighboring domains, aberrantly activating proto-oncogenes while simultaneously altering local landscapes to sustain the rewired interactions. Such events highlight the causal links between epigenetic-3D crosstalk and , where phase-separated domains driven by marks may either buffer or amplify these pathogenic changes.

Gene Expression Regulation

Repression and Activation Mechanisms

Epigenetic modifications orchestrate gene activation through coordinated changes in accessibility and transcriptional machinery recruitment. Hypomethylation of promoter CpG islands reduces steric hindrance and recruits transcription factors, while histone acetylation, particularly of H3 and H4 tails by enzymes such as p300/CBP, neutralizes positive charges on histones, leading to decompaction and enhanced DNA accessibility. This open state facilitates the binding of sequence-specific transcription factors, which in turn recruit complex—a multi-subunit coactivator that bridges enhancers and promoters. complex interacts directly with (Pol II) within the preinitiation complex, stabilizing its association with promoter DNA and promoting of the Pol II C-terminal domain by CDK7/TFIIH to initiate transcription elongation. In contrast, gene repression is mediated by hypermethylation of CpG islands, which recruits methyl-CpG-binding proteins that tether histone deacetylases and other repressors, compacting and inhibiting access. Concurrently, trimethylation of at 27 (H3K27me3), catalyzed by the Polycomb repressive complex 2 (PRC2) containing , promotes compaction and higher-order folding. This repressive mark is recognized by Polycomb repressive complex 1 (PRC1), which ubiquitinates at 119 (H2AK119ub), further stabilizing compact structures and blocking Pol II progression by inhibiting its elongation through repressive domains. These mechanisms collectively enforce transcriptional silencing by creating physical barriers to Pol II recruitment and processivity. The combinatorial logic of epigenetic marks enables nuanced control, as exemplified by bivalent domains in embryonic stem cells, where promoters of developmental genes bear both activating (deposited by MLL complexes) and repressive marks. This duality maintains genes in a transcriptionally paused, poised state, preventing premature expression while allowing rapid resolution upon differentiation signals—typically by loss of to activate lineage-specific genes.00380-1) Such bivalency highlights how opposing modifications on the same nucleosomes balance repression and potential activation, ensuring developmental plasticity. Feedback loops reinforce these states during active transcription, where elongating Pol II recruits histone chaperones like the FACT complex (facilitating transcription), which temporarily displaces H2A-H2B dimers to allow passage and subsequently reassembles nucleosomes with acetylated s, perpetuating an open configuration. In repressive contexts, propagation by PRC2 creates self-sustaining loops by recruiting additional PRC1, maintaining compaction. Quantitative aspects of these processes often involve threshold effects, where the density of marks—such as sufficient levels of exceeding a critical threshold—triggers phase-separated domains that switch genes to stable off states, while subthreshold densities permit poised or low-level expression.00700-8) This digital-like switching ensures robust, all-or-nothing gene regulation essential for cellular identity.

Developmental Roles

The epigenome undergoes dynamic reprogramming during early embryonic development, characterized by waves of genome-wide demethylation followed by de novo methylation to establish cell-specific identities. Upon fertilization, the paternal genome experiences rapid active demethylation via TET3-mediated oxidation of 5-methylcytosine, while the maternal genome undergoes passive demethylation through replication-dependent dilution, facilitating zygotic genome activation (ZGA) around the 2- to 8-cell stage in mammals. This initial erasure of parental epigenetic marks allows for totipotency but is followed by de novo methylation waves, with the first occurring at the 1-cell stage on the paternal pronucleus and the second from the 4- to 8-cell stage, mediated by DNMT3A and DNMT3L, to protect imprinted loci and initiate lineage priming. These reprogramming events ensure the transition from maternal to zygotic control and set the stage for subsequent differentiation. Epigenetic modifications serve as barriers that stabilize cell fate decisions, preventing inappropriate and maintaining lineage fidelity during development. For instance, stable and repressive marks like at lineage-specific genes create epigenetic roadblocks that resist reprogramming to alternative states, ensuring irreversible commitment to , , or lineages. In clusters, which dictate anterior-posterior body patterning, activation during involves progressive acquisition of active marks such as and H3K27ac at enhancers, coordinated by Trithorax group proteins, while Polycomb repressive complex 2 (PRC2) maintains to silence non-expressed clusters. These states thus orchestrate spatiotemporal HOX expression critical for somitogenesis and limb development. Genomic imprinting and X-chromosome inactivation (XCI) exemplify parent-of-origin-specific epigenetic regulation essential for development, primarily through differential at imprinting control regions (ICRs). Imprinted genes, such as Igf2 and H19, exhibit allele-specific established in gametes and maintained post-fertilization, influencing fetal growth and placental function via monoallelic expression. In females, imprinted XCI silences the paternal in extra-embryonic tissues, mediated by maternal at the promoter to repress the on the maternal allele, while Tsix, an antisense repressor, prevents ectopic upregulation on the active X. Random XCI in the proper, triggered by upregulation and subsequent spreading, equalizes X-linked dosage and is stabilized by at promoters.00205-5) These mechanisms ensure dosage compensation and avoid developmental lethality from biallelic expression. Environmental factors during fetal development can induce lasting epigenetic alterations in the epigenome, with teratogen exposure disrupting normal patterns and leading to persistent phenotypic traits. Prenatal exposure to endocrine disruptors like or such as alters global and in fetal tissues, affecting genes involved in and neurodevelopment, with effects persisting into adulthood via transgenerational in some cases. For example, alcohol as a teratogen causes hypermethylation at neural genes, contributing to fetal alcohol disorders with lifelong cognitive impairments. These changes highlight the epigenome's plasticity as a mediator of environmental programming . In pluripotent stem cells, the epigenome maintains the core pluripotency network through hypomethylated enhancers accessible to key transcription factors like Oct4 and . Oct4 and Sox2 cooperatively bind to composite motifs in distal enhancers of pluripotency genes (e.g., Nanog, Sall4), where low and open —marked by H3K4me1 and H3K27ac—facilitate autoregulatory loops that sustain self-renewal and prevent premature differentiation. This hypomethylated state at super-enhancers amplifies expression of the pluripotency circuitry, while /3 enzymes protect essential loci from de novo methylation during cell divisions. Upon differentiation cues, enhancer remodeling closes these regions, locking in lineage-specific epigenomes.

Clinical and Biological Significance

Role in Cancer

Epigenetic alterations are a hallmark of cancer, contributing to tumorigenesis through dysregulation of , modifications, and structure. Global DNA hypomethylation, observed in most cancer types, leads to genomic instability by promoting chromosomal rearrangements and activating oncogenes, while regional hypermethylation at promoter CpG islands silences tumor suppressor genes. For instance, in gliomas, hypermethylation of the promoter impairs and enhances sensitivity to alkylating agents like . Similarly, in , promoter hypermethylation inactivates the tumor suppressor, facilitating Wnt pathway activation and adenoma formation early in . Histone modifications also play critical roles in oncogenic processes. Mutations in , the catalytic subunit of the Polycomb repressive complex 2 (PRC2), result in aberrant H3K27 hypermethylation, which represses tumor suppressor genes and drives lymphomagenesis; these gain-of-function mutations occur in over 25% of cases and represent an early clonal event. In solid tumors, overexpression of histone deacetylases (HDACs), particularly classes I and II, correlates with poor prognosis by maintaining repressive states that promote proliferation and survival, as seen in , , and colorectal cancers. Therapeutic targeting of these epigenetic changes has yielded clinical successes. DNA methyltransferase inhibitors (DNMTi) like , approved by the FDA in 2004 for myelodysplastic syndromes (MDS), reactivate silenced genes by inducing hypomethylation and have extended overall survival in higher-risk MDS patients. HDAC inhibitors such as , approved in 2006 for (CTCL), induce hyperacetylation to disrupt oncogenic signaling and promote , with response rates up to 30% in relapsed CTCL. In cancer stem cells (CSCs), which drive tumor initiation and resistance, the epigenome maintains self-renewal through bivalent chromatin domains—regions marked by both (activating) and (repressive)—that poise developmental genes for rapid activation, as observed in and breast CSCs.

Role in Aging

The epigenome undergoes progressive alterations during aging, often referred to as epigenetic drift, which contributes to the decline in cellular function and organismal health. A key manifestation is the development of epigenetic clocks, such as the Horvath clock introduced in 2013, which estimates biological age based on levels at 353 specific CpG sites across various tissues and cell types. This clock reflects the cumulative impact of an epigenetic maintenance system, where deviations from chronological age indicate accelerated or decelerated aging processes. Epigenetic drift in aging is characterized by stochastic changes in DNA methylation patterns, including widespread loss of methylation (hypomethylation) at global levels and gains at specific promoter regions, alongside erosion of due to loss. These shifts create epigenetic mosaicism, particularly in post-mitotic tissues and stem cells, leading to loss of cellular identity and function. Underlying mechanisms include reduced activity of DNA methyltransferases (DNMTs), such as , which diminishes maintenance methylation fidelity over time. Oxidative stress further induces aberrant epigenetic marks, like altered modifications, while contributing to shortening through damage to telomeric . These epigenetic changes drive age-related consequences, including chronic low-grade inflammation (inflammaging) via sustained pathway activation, which promotes pro-inflammatory . Additionally, they contribute to stem cell exhaustion by impairing self-renewal and differentiation capacities through disrupted landscapes and increased mosaicism. Interventions like caloric restriction have been shown to mitigate these effects in animal models, slowing the progression of epigenetic clocks and reducing drift to extend healthspan.

Implications for Disease and Therapy

Aberrant DNA methylation patterns have been implicated in neurological disorders such as , where hypomethylation of the amyloid precursor protein (APP) gene promoter correlates with increased APP expression and amyloid-beta plaque formation in affected brain regions. In , deficits in histone acetylation, particularly reduced activity of the (CBP) , lead to transcriptional dysregulation of neuronal genes, exacerbating neurodegeneration and cognitive impairments. Similarly, metabolic diseases like involve persistent epigenetic alterations in adipocytes, including loss of lysine 4 trimethylation () at genes regulating and , which maintains a pro-inflammatory state even after . Emerging therapeutic strategies leverage CRISPR-based epigenome editing to modulate these marks precisely, such as fusing deactivated (dCas9) with DNA methyltransferases (DNMTs) to induce targeted methylation and silence disease-associated genes, with developments accelerating in the through proof-of-concept studies in cellular models. RNA therapeutics targeting long non-coding RNAs (lncRNAs) offer another avenue, as antisense can disrupt lncRNA-mediated recruitment of epigenetic complexes to restore balanced in dysregulated pathways. Key challenges in these approaches include off-target epigenetic modifications from editors, which may alter unintended genomic loci and cause pleiotropic effects, alongside concerns over the reversibility of induced changes in dynamic cellular contexts. Preclinical studies exploring epigenetic therapies for imprinting disorders like Prader-Willi syndrome focus on small-molecule inhibitors and -based approaches to reactivate silenced genes, with clinical trials in early phases for related conditions like . Recent preclinical advances, such as -mediated activation of the imprinted Prader-Willi syndrome locus published in 2025, highlight potential for stable gene reactivation. In , epigenomic profiling—such as genome-wide arrays—enables prediction of drug responses by identifying patient-specific marks that influence and therapeutic outcomes, guiding tailored interventions.

Research and Methods

Major Projects and Consortia

The () project, launched in 2003 by the (), initially focused on identifying functional elements in the but expanded significantly into to map states and across diverse cell types. By integrating epigenomic assays, generated comprehensive profiles for over 400 biologically and medically relevant human cell types as of recent updates, providing a foundational resource for understanding regulatory landscapes. The NIH Roadmap Epigenomics Mapping Consortium, active from 2008 to 2015, built upon ENCODE's efforts by producing reference epigenome maps for 111 primary human tissues and cell types, incorporating modifications, DNA accessibility, and data. This identified approximately 2.3 million putative enhancer regions across the , highlighting their role in tissue-specific gene regulation and conserved non-coding elements. Established in 2010, the International Human Epigenome Consortium (IHEC) coordinates global efforts to generate and standardize high-resolution reference epigenomes for both normal and diseased cell states, emphasizing of datasets from multiple international projects. IHEC has facilitated the release of over 1,000 reference epigenomes, including those from diseased tissues, through a unified data portal to support cross-project analyses and disease-relevant research. These initiatives have yielded comprehensive epigenomic atlases that reveal tissue-specific regulatory marks, such as differential enhancer usage across cell types, and have enabled key discoveries like super-enhancers—clusters of enhancers driving cell identity genes and implicated in diseases including cancer. A notable recent expansion within IHEC is the BLUEPRINT project (2011–2016), which focused on hematopoietic cell epigenomes to address blood disorders, generating maps for over 100 types from healthy and leukemic samples to inform and studies. ENCODE continues to evolve, with ongoing phases adding more cell types and assays. In 2024, the announced a new initiative, "Beyond the Genome," to map DNA modifications and activity across the human lifespan, building on prior efforts to study aging and developmental changes.

Current Techniques and Advances

remains the gold standard for mapping at single-base resolution across the . This technique involves treating DNA with , which deaminates unmethylated cytosines to uracils while leaving methylated cytosines intact, followed by PCR amplification and next-generation sequencing to detect patterns. Whole-genome (WGBS) extends this to comprehensive coverage, enabling quantitative assessment of (5mC) levels at CpG sites and beyond, with applications in identifying differentially methylated regions associated with . Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is a cornerstone method for profiling modifications and other -associated proteins. In ChIP-seq, antibodies specific to marks such as (active promoters) or (repressive domains) are used to immunoprecipitate protein-DNA complexes, which are then sequenced to map enrichment genome-wide. This approach has revealed the combinatorial nature of codes in defining epigenomic landscapes, with peak calling algorithms identifying binding sites at nucleotide resolution. Complementing ChIP-seq, assay for transposase-accessible with sequencing (ATAC-seq) assesses accessibility by using hyperactive Tn5 to insert adapters into open regions, providing insights into regulatory element activity without requiring antibodies. ATAC-seq offers high sensitivity for low-input samples and has been instrumental in annotating enhancers and insulators in diverse cell types. Advances in single-cell epigenomics have enabled resolution of epigenetic heterogeneity across individual cells, addressing limitations of bulk assays that average signals. Single-cell bisulfite sequencing (scBS-seq), developed in the 2010s, adapts bisulfite conversion for low-input DNA, achieving coverage of up to 48.4% of CpG sites per cell and revealing cell-to-cell variability in methylation patterns during development and disease. More recent methods, such as T7-assisted enzymatic methylation sequencing (TEAM-seq) introduced in 2022, have improved coverage to up to 70% for single cells, enhancing the detection of epigenetic variation. Spatial epigenomics techniques, such as those integrating multiplexed error-robust fluorescence in situ hybridization (MERFISH) with epigenomic labeling, allow visualization of histone marks in tissue context, mapping active and repressive states at subcellular resolution to uncover spatial organization of epigenomic domains. These methods, often combined with single-cell RNA-seq, facilitate integrated multi-omics profiling of tissue architecture. Epigenome editing tools based on CRISPR-Cas9 have emerged for precise manipulation of epigenetic marks, enabling causal studies of their regulatory roles. By fusing deactivated (dCas9) to epigenetic effectors like TET1 for or p300 for , researchers demonstrated targeted installation of marks at specific loci as early as 2015-2016, activating endogenous genes from promoters and enhancers with minimal off-target effects. As of 2025, these tools have advanced toward clinical applications, with strategies for treating complex diseases through reversible modulation of . Computational tools, particularly models, have advanced the prediction of epigenomic states directly from DNA sequence, reducing reliance on experimental assays. architectures, such as convolutional neural networks in models like DanQ, integrate sequence motifs and long-range dependencies to forecast modifications and accessibility with high accuracy, achieving correlations exceeding 0.8 for key marks like H3K27ac. These approaches leverage large epigenomic datasets from projects like to train predictive models, aiding in variant interpretation and enhancer discovery across species.

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