Hello, this repo aims at summarizing all the current knowledge about Epigenetics. If you are interested to contribute, please contact hongleir@uci.edu, we are looking forard your expertise.
- Literature Review on Epigenetics
- Introduction
- Epigeneitics
- Molecular Mechanisms of Epigenetics
- Genomic Landscape of Epigenetics in Somatic Cells
- Epigenetic Technology
- Analyses of Gene-specific DNA Methylation
- Methods for Assessing Genome-wide DNA Methylation
- Determination of Histone Modifications of Specific Genes
- Analyses of Genome-wide Histone Modifications
- Techniques for Genome-wide Expression of Non-coding RNA
- Techniques of Genome-wide Nucleosome Positioning
- Analyses of Genome-wide Nucleosome Positioning
- Techniques of Genome-wide 3D Chromatin Structure
- Analyses of Genome-wide 3D Chromatin Structure
- Computational Epigenetics
- Functions of Epigenetics
- Model Organisms of Epigenetics
- Epigenetics and Human Disease
- Single Cell Epigenetics
- Sequencing Techniques of Single Cell Epigenetics
- Computational Methods of Single Cell Epigenetics
- Multi-omics
- Epigenetic Epidemiology
- Metabolism and Epigenetics
- Epigenetic Therapy
- Evolutionary Epigenetics
- The Future of Epigenetics
- Reference
In 1942, Waddington coined the term epigenetics, which he defined as changes in phenotype without changes in genotype, to explain aspects of development for which there was little mechanistic understanding [138, 139].
The major epigenetic signals include DNA methylation and demethylation, covalent post-translational reversible modifications of the histone proteins, such as acetylation, methylation, phosphorylation and ubiquitination, incorporation of histone variants and gene regulation by non-coding RNAs [88].
Epigenetic mechanisms work in addition to the DNA template to stabilize gene expression programmes and thereby canalize cell-type identities [140]. The genetic message is differentially decoded in both time and space as a result of epigenetic constraints on the genome resulting either in gene activation or silencing[85].
Pioneering work carried out between 1869 and 1928 by Miescher, Flemming, Kossel and Heitz defined nucleic acids, chromatin and histone proteins, which led to the cytological distinction between euchromatin and heterochromatin [141] (Fig.3a). This was followed by ground-breaking studies by Muller [142] (in Drosophila melanogaster) and McClintock [143] (in maize) on position-effect variegation (PEV) and transposable elements, providing early hints of non-Mendelian inheritance. Descriptions of the phenomena of X-chromosome inactivation [144] and imprinting [145, 146] subsequently led to the general concept that identical genetic material can be maintained in different on versus off states in the same nucleus, but its underlying mechanisms were poorly understood.
Figure 3. Euchromatin and heterochromatin. a | Cytologically visible ground states of active (euchromatic) and repressed (heterochromatic) chromatin. Schematic representation of two interphase nuclei from female mouse somatic cells: the left nucleus displays broad and decondensed staining of unique DNA sequences and the right nucleus shows the characteristic heterochromatic foci (black dots) that are visualized by DAPI (4′,6-diamidino-2-phenylindole) staining of AT-rich repeat sequences. In addition, the densely staining Barr body (an inactive X chromosome (Xi)) at the nuclear periphery is indicated. In the early years, cytologists used various chromatin dyes and DNA-binding fluorochromes to discriminate euchromatic (decondensed and light staining) from heterochromatic (compact and dense staining) regions in eukaryotic chromatin. b | Enzymatic definition of chromatin states that stimulate gene activity (histone acetylation by p55 (also known as Gcn5)) or repress gene activity (histone methy- lation by Su(var)3–9 homologue 1 (SUV39H1)). In 1996, the nuclear histone acetyltransferase (HAT) p55 from Tetrahymena thermophila was described as a transcriptional co-activator that acetylates the histone H3 amino-terminal tail. The acetylated (Ac) lysine on H3 (H3K14ac) provides a docking site for bromodomain (Bromo)-containing accessory proteins that bind to and further stimulate nucleosome accessibility and transcriptional activity. Histone acetylation can be reversed by opposing histone deacetylases (HDACs), which often cause transcriptional repression. In 2000, the human histone lysine methyltransferase (KMT) SUV39H1 was described as an orthologue of a Drosophila melanogaster Su(var) position-effect variegation factor that methylates the histone H3 N-terminal tail. The trimethy- lated H3K9 (H3K9me3) provides a docking site for the chromodomain (Chromo)-containing hetero- chromatin protein 1 (HP1), which then impairs nucleosome accessibility and induces gene repression. The reversibility of histone lysine methylation was not known at that time. (Figure from Ref.[140])
In the mid-1960s, pioneering work of Allfrey [159] on histone modifications, in particular histone acetylation, led to the hypothesis that acetylation is closely linked to gene activity [160]. Many studies followed, including studies by Grunstein and others on histone-tail mutations in Saccharomyces cerevisiae that perturb gene silencing at telomeres and mating-type loci; this seminal work provided early functional evidence, including the first characterization of silent information regulator proteins [161, 162]. Development of modification- or site-specific antibodies (for example, histone 4 lysine 16 acetylation (H4K16ac)) by Turner and others documented non-random patterns of histone acetylation, such as hypoacetylation of the inactive X chromosome in female mammals [163] or the silent mating type genes in yeast [164], as well as hyperacetylation of the twofold upregulated X chromosome in D. melanogaster males [165] or expressed [166] β-globin genes in chicken red blood cells .These major discoveries made a compelling argument that histone modifications, in addition to DNA methylation, carry information that can distinguish euchromatin from heterochromatin. Powerful genetic screens in flies [167, 168, 169], yeast [170, 171] and plants [168, 172] had identified other key factors for chromatin- dependent gene regulation, such as heterochromatin protein 1 (HP1), Suppressor of variegation 3–9 (Su(var)3–9), Enhancer of zeste (E(z)), Polycomb, Trithorax, cryptic loci regulator 4 (Clr4) and DECREASED DNA METHYLATION 1 (DDM1).
In 1996, Allis and colleagues purified and cloned the first histone acetyltransferase(HAT) - p55 from T. thermophila (Fig.3b) [173]. Strikingly, this ciliate HAT (p55) was an orthologue of the previously described transcriptional coactivator Gcn5 from budding yeast, providing a direct link between histone acetylation and gene activation. Other HATs were identified, including TAF1(TATA-box binding protein associated factor TFIID subunit 1, also known as TAF(II)250) [174], PCAF(p300/CBP-associated factor) [175] and CBP/p300 (CREB-binding protein and p300)[176, 177], thus confirming and extending this paradigm to mammalian cells [178].
Approximately one month after the publication of the p55–Gcn5 HAT results [173], Schreiber and colleagues [179] reported the purification and cloning of the first histone deacetylase (HDAC), and it was found to be an orthologue of the budding yeast transcriptional co-repressor Rpd3 (Fig.3b), which indicated that histone deacetylation is linked to transcriptional repression. In 2000, Guarente and colleagues [180] demonstrated that a critical protein required for gene silencing in yeast, Sir2, was a NAD-requiring HDAC (Fig.4). Subsequently, seven Sir2-like enzymes were identified in mammalian cells, which are now known as the Sirtuin protein family. The Sir2-related HDACs triggered much research interest for their functions in metabolism and ageing, which are still under intense investigation today [181].
In 1999, Zhou and colleagues [182] documented the bromodomain from PCAF as an acetyl-lysine binding module for docking onto acetylated histones. This was the first histone-modification-binding domain to be described, suggesting a novel mechanism (trans-effects) for the binding of bromodomain-containing factors to acetylated targets in chromatin. To date, a multitude of chromatin-binding modules have been described, many in atomic resolution with their cognate modified-histone ligands [178, 183].
The discovery of the first histone lysine methyltransferase (KMT) containing an evolutionarily conserved SET domain, identified by Reuter [184], and mammalian orthologues cloned and characterized by Jenuwein [185]. The SET domain is present in Su(var)3–9 (Suppressor of variegation 3–9, a histone H3 lysine 9 (H3K9) methylating enzyme), E(z) (Enhancer of zeste, a histone H3 lysine 27 (H3K27) methylating enzyme) and Trithorax (a histone H3 lysine 4 (H3K4) methylating enzyme) proteins, all of which had been implicated in epigenetic regulation without evidence of enzymatic activity.
Histone arginine methylation has been associated with gene regulation, as the co-activator CARM1 (coactivator-associated arginine methyltransferase 1)[186] or the PRMT1(protein arginine N-methyltransferase 1) [187] can mediate hormone-dependent transcriptional stimulation via H3R17 [188] or H4R3 methylation [187].
Figure 4. Timeline of major discoveries and advances in epigenetic research between 1996 and 2016. (Figure from Ref.[140])
Histone tails undergo a variety of covalent modifications including acetylation, methylation, phosphorylation, ubiquitination, and sumoylation, regulating key cellular process such as gene transcription, DNA replication, and DNA repair [113, 114].
DNA methylation was first discovered in calf thymus DNA by Hotchkiss, in 1948 [96], and a role for DNA methylation, in particular for 5-methylcytosine (5mC), in gene regulation was proposed in the mid-1970s by Holliday and Pugh [147], among others. By 1980, the functional connection between DNA methylation and gene repression was established [148], as was the existence of CpG islands [149]. The first 'epigenetic drug', 5-azacytidine (also known as 2′-deoxy-5-azacytidine and later called decitabine), which blocks DNA methylation, was used to alter gene expression and phenotypes in fibroblast cell lines [150]. Soon thereafter, Feinberg and Vogelstein [151] reported global DNA hypomethylation in cancer and, a decade later, local DNA hypermethylation of tumour suppressor genes was described — findings that were collectively reviewed [152]. These insights gave a compelling reason to pursue the ‘enzymology’ of DNA methylation. The successful purification and cloning of the mouse DNA (cytosine-5)-methyltransferase 1 (DNMT1) enzyme [153, 154] and the generation and analysis of Dnmt1-mutant mice [105] proved important advances towards this goal. During the same time frame, the first DNA-methyl-binding protein, MeCP2 (methyl-CpG-binding protein 2), was identified [155]. DNA methylation and 5mC (considered the ‘fifth base’) had been firmly established as a crucial epigenetic mechanism in many, but not all, organisms.
DNA methylation is a heritable epigenetic mark involving the covalent transfer of a methyl group to the C-5 position of the cytosine ring of DNA by DNA methyltransferases 1 (DNMTs) [91]. DNA methylation is well conserved among most plant, animal and fungal models[2]. In prokaryotes, DNA methylation takes place on both cytosine and adenine bases and constitutes a branch of the host restriction system to distinguish self and non-self DNA. However in multicellular eukaryotes this modification is limited to cytosine bases only and acts mainly as a repressive tag resulting in silent chromatin state and transcriptional repression [97, 98]. In mammals, DNA methylation occurs at cytosines in any context of the genome. In plants, cytosines are methylated in both symmetrical (CG or CHG) or asymmetrical (CHH, where H is A, T, or C) contexts [95]. However, more than 98% of DNA methylation occurs in a CpG dinucleotide context in somatic cells [3, 4], while as much as a quarter of all methylation appears in a non-CpG context in embryonic stem cells (ESCs) [95].
Most DNA methylation is essential for normal development, and it plays a very important role in a number of key processes including genomic imprinting, X-chromosome inactivation, and suppression of repetitive element transcription and transposition and, when dysregulated, contributes to diseases like cancer [91, 92, 93, 94]. It is considered to be one of the first steps in epigenetic regulation, acting as a fundamental mechanism in functional organization of the human genome. It is also an attractive and promising target in the development of new drugs for cancer chemotherapy as epigenetic alterations are, in principle, more readily reversible than genetic anomalies [88].
Studies by many groups led to the widely accepted model of nucleosomal organization of chromatin [156], which was first articulated in a provocative theory — the chromatin subunit model — put forward in 1974 [157] and visualized by the landmark X-ray crystal structure of the histone octamer–DNA particle in 1997 [158]. As was shown, the basic unit of the chromatin fibre is the nucleosome core particle, which is composed of two copies each of four histone proteins (a histone octamer) that package 147 bp of DNA.
- What are the roles of the epigenetic marks?
- How are they coordinated in normal development and disrupted in disease?
Methylation of DNA is a post synthetic process catalyzed by a family of dedicated enzymes known as DNA by DNMTs(DNA methyltransferases). DNMT1, DNMT3A and DNMT3B methylate the cytosine residue in the presence of cofactor SAM (S-Adenosyl methionine), which donates the –CH3 group and is converted to SAH (S-Adenosyl homocysteine) [86, 101].
It has been widely believed that DNMT1 acts mainly as a maintenance methyltransferase during DNA synthesis and that DNMT3A and DNMT3B act as de novo enzymes in development. However, mounting evidence indicates that DNMT1 may also be required for de novo methylation of genomic DNA19 and that DNMT3A and DNMT3B contribute to maintenance methylation during replication [109, 110].
- DNMT1
DNMT1 preferentially methylates hemi-methylated DNA in vitro and is localized to replication foci during S phase.
Mouse models with both alleles of Dnmt1 deleted are embryonic lethal at approximately day E9 [104, 105].
- DNMT3A, DNMT3B
DNMT3A and DNMT3B have preference for unmethylated CpG dinucleotides and perform de novo methylation during development. Mice lacking DNMT3A die at about 4 weeks of age, whereas DNMT3B knockout induces embryonic lethality at E14.5 to E18.5 [104, 106].
- DNMT3L
DNMT3L assists the DNMT3A/3B by increasing their ability to bind to the methyl group donor, S-adenosyl-Lmethionine (SAM), and stimulating their activity in vivo, although DNMT3L has no catalytic activity itself [107].
Dnmt3L homozygous-null mice are viable, whereas heterozygous embryos derived from homozygous Dnmt3L-null oocytes die around E9 and display impaired maternal methylation imprints and biallelic expression of imprinted genes normally expressed only from the allele of paternal origin [108].
During mammalian development and cancer, DNA methylation and specific histone modifications appear to reciprocally influence each other in deposition: histone methylation may direct DNA methylation patterns (Fig.1), and DNA methylation may serve as a template for the establishment of certain histone modifications (Fig.2) after DNA replication [113].
Figure 1. How the histone code may direct DNA methylation during development and carcinogenesis. (A) During normal development, the transcriptionally activating mark H3K4 me3 (x) blocks or repels DNMTs, whereas the repressive marks H3K9me or H3K27me (y) permit or recruit DNMTs, possibly by direct protein-protein interactions (e.g., EZH2-DNMTs). During carcinogenesis, disruption of the histone code in the form of (B) loss of H3K4me3 (x), (C) substitution of H3K4me3 with H3K9me or H3K27me (y), randomization of marks, aberrant acquisition of a new mark (z), or (D) loss of all histone marks permits or actively induces DNMT recruitment. x = H3K4me3; y = H3K9me or H3K27me; z = other histone mark; bent arrow = transcription start site; lollipops = histone marks; black circles = DNA methylation. (Figure from Ref.[89])
There is also evidence that DNA methylation directs H3K9me2/3, although this remains controversial. Hypomorphic mutation of DNMT1 gene causes a global reduction of H3K9me2/3 levels in a cancer cell line; re-expression of DNMT1 rescues this phenotype [128, 129]. Dnmt1 and Dnmt3b double knockout in colon cancer cells induces changes in H3K9 methylation levels at heterochromatin and specific tumor suppressor loci [130]. Triple knockout (TKO) of Dnmt1/Dnmt3a/Dnmt3b in ESCs results in complete loss of DNA methylation at several repetitive sequences and imprinted genes [131]; however, TKO ES cells retain occupancy of H3K9 methylation and HP-1 in pericentromeric regions [131]. The link between DNA methylation and H3K9 methylation is via interaction of the enzymes mediating these marks. DNMT1, for example, directly binds G9A both in vivo and in vitro, and these two proteins colocalize in H3K9 methylation at replication foci during DNA replication. Depletion of DNMT1 not only impairs DNA methylation but also retards G9A loading and H3K9 methylation on chromatin and rDNA repeats [128]. Similarly, heterochromatic colocalization of SUV39H1 and DNMT1 exists exclusively before cell division.
Figure 2. How the histone code may rely on the DNA methylation machinery for direction. Upon binding to CpG-rich regions, DNMTs may directly recruit HMTs to these domains. During DNA replication, UHRF1 preferentially binds hemimethylated DNA and interacts with/ recruits DNMT1 and G9A. PCNA may also have a role in the recruitment process. Methyl-CpG– binding proteins (MBDs) specifically interact with methylated DNA and may form complexes with HMTs such as SETDB1 to direct histone methylation to regions of DNA methylation.(Figure from Ref.[89])
Yet an additional link between DNA methylation and the histone code exists via the methyl-CpG–binding proteins (MBDs), which interact specifically with methylated DNA and mediate transcriptional repression (Fig.2). During replication of DNA methylation-rich regions of the genome, CAF1 forms a complex with MBD1 and the histone lysine methyltransferase SETDB1, thereby coupling histone methylation with DNA methylation [125]. MBD1 deletion suggest that H3K9 methylation mediated by SETDB1 is dependent on MBD1, which recruits SETDB1 to CAF1 at active replication forks [132].
The two global mechanisms of gene regulation, DNA methylation and histone deacetylation, are also linked via the methyl-CpG– binding protein MeCP2. MeCP2 binds tightly to chromosomes in a DNA methylation–dependent manner. It contains a transcriptional-repression domain (TRD) that functions at a distance in vitro and in vivo, and MeCP2 associates with a corepressor complex containing histone deacetylases [133].
H3K9me3, H3K27me3 and H4K20me3 has been suggested to be a prerequisite for subsequent DNA methylation, which appears to be attributable to physical associations between the components of these histone methylation systems and one or more DNMTs (Fig.1). In the context of H3K9 and H3K27, the relevant histone lysine methyltransferases, SUV39H1/2 and EZH2, respectively, interact directly with DNMT1, DNMT3A, and DNMT3B [115, 116]. Pericentromeric localization of DNMT3B depends on SUV39H1/2-mediated H3K9 dimethylation or trimethylation [115]. SUV39H1/2 double-null murine embryonic stem cells display reduced DNA methylation levels at major satellite repeats but not at minor satellites or endogenous C-type retroviral elements [116]. Endogenous DNMT1 and DNMT3A also associate with H3K9 methyltransferase SUV39H1 activity as well, mediated by the conserved PHD-like motif in the case of DNMT3A [117].
The binding of HP1 to constitutive heterochromatin depends on the enzymatic activity of SUV39H1/2, which catalyze H3K9me3 [122], while HP1 binding to euchromatin depends on dimethylation of H3K9 mediated by G9A [118]. Methylated H3K9 serves as a binding platform for HP1 to associate with the DNA methylation machinery. HP1 binds directly to the PHD-like motif of DNMT3A in vitro [117]. The direct physical link identified between the DNMTs and the H3K9me-HP1 system therefore ensures that H3K9 methylation directly influences DNA methylation patterns [115, 117].
HP1(heterochromatin protein 1) proteins modulate gene transcription in both euchromatin and heterochromatin. HP1 binds to methylated H3K9 through its N-terminal chromo-domain. HP1 proteins also recruit a variety of other factors including histone deacetylases, transcriptional repressors, and chromatin remodeling enzymes to the methylated region to further enhance and/or stabilize repressive domains [91, 124].
EZH2, one of the core components of polycomb repressive complex 2 (PRC2), catalyzes H3K27me3, which acts subsequently to recruit the PRC1 complex and mediate transcription silencing. EZH2 physically interacts with the DNMTs and facilitates their binding to certain EZH2 target promoters [116]. Overexpression of EZH2 increases CpG methylation, while RNA interference knockdown of EZH2 reduces H3K27 methylation and DNA methylation at known EZH2 target genes [116].
The G9A/GLP heteromeric complex induces both H3K9 and DNA methylation on G9A target loci, and these two epigenetic marks cooperatively suppress transcription of their target genes. Tachibana et al. showed that promoter regions of G9A/GLP target genes are DNA hypomethylated in G9a or Glp knockout ESCs [118].
Histone arginine methylation has also been linked to DNA methylation and gene silencing [119]. Symmetric dimethylation of histone H4 arginine 3 (H4R3me2s), catalyzed by PRMT5, serves as a direct binding target for DNMT3A, which may then induce methylation of adjacent CpG dinucleotides at PRMT5 target genes [119].
Direct interactions between HP1 and DNMT1 mediate silencing of euchromatic genes [123]. Silencing of the survivin gene coincides with recruitment of G9A and HP1 in DNMT1 wild-type but not DNMT1-null cells [123]. Binding of GAL4-HP1 to a reporter construct is sufficient to induce repression and DNA methylation in DNMT1 wild-type but not DNMT1-null cells [123].
In addition to the direct recruitment of DNMTs, histone methyltransferases and demethylases may also influence the stability of DNMT proteins [120]. SET7, a known histone methyltransferase for H3K4, colocalizes with DNMT1 and methylates DNMT1 at the K142 position to regulate its stability and degradation. Overexpression of SET7 leads to decreased DNMT1 levels, and siRNA-mediated knockdown of SET7 stabilizes DNMT1 [120]. Lysine-specific demethylase 1 (LSD1) has been shown to demethylate histone H3K4 and H3K9. LSD1 also demethylates DNMT1 methylated at K142 to antagonize the effect of SET7 [121].
Chromatin, rather than naked DNA, is the substrate for all processes that affect genes and chromosomes. Nucleosomes form the fundamental repeating unit of eukaryotic chromatin, serving as the basic module for DNA packaging that regulates the accessibility of DNA to interacting proteins and alters transcriptional states [189].
Studies have revealed that nucleosomal DNA is an important substrate for the DNMTs [190, 191]. Genome-wide nucleosome positioning analysis in human cells showed that DNA methylation is enriched in nucleosome-bound DNA rather than linker DNA, indicating that nucleosome-bound DNA is a preferred substrate for DNA methylation [191]. Jeong et al reported that DNMT3A and DNMT3B are strongly anchored to nucleosomes, whereas DNMT1 interacts primarily with linker DNA [190]. Deletion experiments demonstrated that the N-terminal region of DNMT3A and DNMT3B, which contains PWWP and PHD-like motifs, plays an essential role in their strong nucleosomal binding [190]. DNMT3A was recently shown to specifically bind the H3K36me3 mark through its PWWP domain, which is important for the subnuclear localization of DNMT3A and suggested that nucleosomal binding of DNMT3A and DNMT3B might, at least in part, be mediated by its interaction with H3K36me3 [192]. Surprisingly, some well-known chromatin-modifying proteins, such as PCNA, HP1, MBD2, EZH2, HDAC1, and UHRF1, are not required for DNMT3A and DNMT3B to bind to nucleosomes [190]. SINE and LINE repetitive elements and CGIs in nucleosomes represent the main binding sites of DNMT3A and DNMT3B, suggesting that additional cues, other than hemimethylated DNA, from the chromatin are needed for inheritance of DNA methylation.
Nucleosome positioning also has a striking effect on DNA methylation. As a linker histone, H1 reduction leads to decreases in nucleosome repeat length, which is a primary determinant of nucleosome spacing [193]. Interestingly, depletion of histone H1 induces DNA hypomethylation of specific CGIs such as the imprinting control regions of the H19-Igf2 and Gtl2-Dlk1 loci [193].
Nucleosome positioning displays a sequence preference characterized by particular dinucleotides, tending to occur periodically throughout the nucleosome with 10-bp periodicity [198]. This sequence preference might arise from the near-circular wrapping of the nucleosomal DNA, which requires sharp bending every helical repeat (10 bp) [198, 199]. DNMTs enter the major groove to access and methylate the cytosine on the outside of the nucleosome (minor groove). As nucleosome-bound DNA shows a 10-bp periodicity in its CG, CHG, and CHH methylation, nucleosomes appear to dictate access to the DNA and therefore set the register of methylation for all DNA methyltransferases.
It is well known that the composition of the nucleosome core particle influences chromatin structure and nucleosome positioning. Emerging evidence has revealed that replacement of the core histones with variants of histone H2A or H3 represents another potential means of gene regulation [194, 195, 196, 197]. The histone H2A variant H2A.Z is excluded from regions of methylated DNA, and H2A.Z enrichment varies inversely with transcription within gene bodies, a finding conserved from plants to animals, indicating that H2A.Z incorporation may contribute to transcriptional activation by protecting genes against DNA methylation [196].
Recent genome-wide studies have revealed that nucleosomes are significantly more enriched in exons compared to introns, consistent with other recent findings of enhanced exonic methylation of gene bodies [200].
DNA methylation obstructs transcriptional activity via two general schemes. First, methylated cytosine bases can hinder the interaction of transcriptional factors and RNA polymerase II with their cognate DNA recognition sequences. Second, methyl-CpG-binding proteins, such as MBD (methyl-CpG-binding domain) proteins, associate with methylated DNA and result in heterochromatin formation by recruiting HDACs (histone deacetylases) [98, 102].
Methylated DNA participates in the formation of chromatin through interactions with various other epigenetic modifications such as the histone code, polycomb complexes, nucleosome positioning, non-coding RNA, and ATP-dependent chromatin remodeling proteins [111].
The epigenetic landscape can vary across genomic regions (spatial heterogeneity), vary within and across cell cycle(temporal heterogeneity), and across cells (cell-to-cell heterogeneity). It grown increasingly complicated, encompassing DNA methylation, the histone code, non-coding RNA, and nucleosome positioning, along with DNA sequence [89].
Mammalian genomes are globally CpG depleted and, of the roughly 28 million CpGs in the human genome, 60–80% are generally methylated. Less than 10% of CpGs occur in CG dense regions that are termed CpG islands; These are prevalent at transcription start sites(TSS) of housekeeping and developmental regulator genes, where they are largely resistant to DNA methylation, i.e. unmethylated [7].
CHIP-seq of CFP1 identified a notable concordance between unmethylated CGIs and H3K4me3 in the mouse brain [134]. Levels of H3K4me3 at CGIs are markedly reduced in CFP1-depleted cells, consistent with the finding that CFP1 associates with the H3K4 methyltransferase SETD1.
DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and may therefore induce de novo DNA methylation by recruitment and activation of DNMT3A2 [37], and this interaction was strongly inhibited by methylation of H3K4 but was insensitive to modifications at other positions. H3K4 methylation may protect certain loci from DNA methylation.
In mammals, there are at least 10 known or predicted H3K4 methyltransferases, which are generally categorized into the MLL (mixed lineage leukemia) family, SET1 family, and others [135]. Disruption of the SET domain of MLL reduced H3K4me1 levels and increased DNA methylation levels at specific loci (e.g., Hoxd4) but not globally in a mouse model [136]. However, forced overexpression of exogenous MLL in MLL knockout cells did not reduce global DNA methylation levels [137].
It is therefore possible that DNA methylation represents a default state of the genome unless H3K4me, or possibly other histone marks, is present to maintain specific regions (e.g., promoters) free of DNA methylation to permit proper gene regulation (Fig.2).
DNA methylation–free CGIs recruit CFP1, and probably other CXXC domain– containing proteins as well, to stimulate methylation of H3K4. Densely methylated CGIs, on the other hand, attract methyl-CpG–binding proteins, which in turn recruit enzymes that reinforce repressive histone marks. CpG islands(CGIs), which are known to recruit Trithorax (TrxG) and Polycomb group proteins.
Bulk of evidence suggests that it is associated with gene activation, and it has been noted in a range of cell and tissue types, and in both plants and animals [203, 204, 205, 206, 207]. Zemach et al analyzed DNA methylation patterns in 17 eukaryotic genomes and showed that gene body methylation is conserved between plants and animals [197].
A few theories have been proposed to explain how intragenic methylation promotes gene expression. One suggests that intragenic methylation represses transcription of the antisense sequence, which may interfere with the expression of the sense gene [111, 208]. An alternative theory proposes that intragenic methylation increases transcriptional efficiency through the repression of cryptic promoters, which are normally silenced promoters found within genes [209]. Experimental evidence supported the repression of cryptic promoters hypothesis came from [210].
Experimentally imposed gene body methylation of an integrated transgene revealed that methylation impaired elongation of transcription in vivo [201].
Figure 5. Intragenic DNA methylation is associated with highly expressed genes. When unmethylated, RNA polymerase II may begin transcription at cryptic promoters. This activity may reduce the transcriptional efficiency of the gene product (Part A). Therefore, intragenic methylation at cryptic promoters may improve transcriptional efficiency (Part B). TSS, transcription start site; RNA pol II, RNA polymerase II.. (Figure from Ref.[211])
There is no obvious template, like the hemi-methylated CpGs in DNA methylation, for nucleosome reassembly after replication. PCNA (proliferating cell nuclear antigen), present at replication forks, plays a very important role both in DNA synthesis, as the polymerase processivity factor, and in the inheritance of epigenetic marks, which may act as a guide for other epigenetic modifications [125]. PCNA recruits a variety of epigenetic regulators such as the histone modifiers HDACs and SETD8, chromatin remodeler SMARCA5, and chromatin assembly factor 1 (CAF1) [125].
The maintenance of DNA methylation at the replication fork is likely ensured by the DNMT1-PCNA and/or DNMT1-UHRF1 interactions. While disruption of the DNMT1-PCNA interaction does little to alter genomic DNA methylation levels, disruption of the DNMT1-UHRF1 interaction results in massive genomic hypomethylation [126], suggesting that UHRF1 is the key player coordinating with DNMT1 to maintain DNA methylation patterns after DNA replication.
UHRF1 preferentially binds to hemimethylated DNA, interacts with DNMT1, and is required for DNMT1 localization to replicating heterochromatic regions [10, 12]. In addition, UHRF1 specifically interacts with peptides that are methylated at H3K9 in vitro [125, 127], and it resides in a complex with HDACs and G9A [10]. Therefore, in addition to binding hemimethylated DNA, UHRF1 appears to interpret the local histone environment, thereby creating a feedback mechanism that involves the mutual reinforcement of histone and DNA methylation marks.
The genomic methylation blueprint is created during two developmental periods—in germ cells and pre-implantation embryos—generating cells with broad developmental potential [99, 100]. Three conserved enzymes, DNA methyltransferase 1 (DNMT1), DNMT3A and DNMT3B, are responsible for its deposition and maintenance and are essential for normal development [5,6].This system of establishing de novo methylation pattern where new methyl marks are added to previously unmethylated cytosines is mainly chaperoned by the de novo methyltransferases DNMT3A and DNMT3B. Maintenance methylation by DNMT1 then ensures that hemi-methylated daughter strands in somatic differentiated cells get methylated to faithfully propagate the proper DNA methylation patterns across successive cell generations [100]. DNA methylation is typically removed (DNA demethylation) during zygote formation, which is essential for cells to return to a pluripotent state, and then re-established in the embryo at approximately the time of implantation [103].
In plants, cytosines are methylated in both symmetrical (CG or CHG) or asymmetrical (CHH, where H is A, T, or C) contexts [95].
Epigenetic hallmarks of cancer include global DNA hypomethylation and locus-specific hypermethylation of CpG islands (CGIs) [111] Hypomethylation arises mainly from loss of methylation at normally heavily methylated repeat elements, including satellites (e.g., SAT2) and retrotransposons (e.g., LINEs), leading to genomic instability and oncogene activation. Locus-specific hypermethylation usually occurs at promoter CGIs of tumor suppressor genes, resulting in heritable transcriptional silencing [89, 112].
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