Pathway: DNA methylation
Reactions in pathway: DNA methylation :
DNA methylation
Methylation of cytosine is catalyzed by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3A, and DNMT3B transfer methyl groups from S-adenosylmethionine to cytosine, producing 5-methylcytosine and homocysteine (reviewed in Klose and Bird 2006, Ooi et al. 2009, Jurkowska et al. 2011, Moore et al. 2013). (DNMT2 appears to methylate RNA rather than DNA.) DNMT1, the first enzyme discovered, preferentially methylates hemimethylated CG motifs that are produced by replication (template strand methylated, synthesized strand unmethylated). Thus it maintains existing methylation through cell division. DNMT3A and DNMT3B catalyze de novo methylation at unmethylated sites that include both CG dinucleotides and non-CG motifs.
DNA from adult humans contains about 0.76 to 1.00 mole percent 5-methylcytosine (Ehrlich et al. 1982, reviewed in Klose and Bird 2006, Ooi et al. 2009, Moore et al. 2013). Methylation of DNA occurs at cytosines that are mainly located in CG dinucleotides. CG dinucleotides are unevenly distributed in the genome. Promoter regions tend to have a high CG-content, forming so-called CG-islands (CGIs), while the CG-content in the remaining part of the genome is much lower. CGIs tend to be unmethylated, while the majority of CGs outside CGIs are methylated. Methylation in promoters and first exons tends to repress transcription while methylation in gene bodies (regions of genes downstream of the promoter and first exon) correlates with transcription (reviewed in Ehrlich and Lacey 2013, Kulis et al. 2013). Proteins such as MeCP2 and MBDs specifically bind 5-methylcytosine and may recruit other factors.
Mammalian development has two major episodes of genome-wide demethylation and remethylation (reviewed in Zhou 2012, Guibert and Weber 2013, Hackett and Surani 2013, Dean 2014). In mice about 1 day after fertilization the paternal genome is actively demethylated by TET proteins together with thymine DNA glycosylase and the maternal genome is demethylated by passive dilution during replication, however methylation at imprinted sites is maintained. The genome has its lowest methylation level about 3.5 days post-fertilization. Remethylation occurs by 6.5 days post-fertilization. The second demethylation-remethylation event occurs in primordial germ cells of the developing embryo about 12.5 days post-fertilization. DNMT3A and DNMT3B, together with the non-catalytic DNMT3L, play major roles in the remethylation events (reviewed in Chen and Chan 2014). How the methyltransferases are directed to particular regions of the genome remains an area of active research. The mechanisms at each locus may differ in detail but a connection between histone modifications and DNA methylation has been observed (reviewed in Rose and Klose 2014).
DNA from adult humans contains about 0.76 to 1.00 mole percent 5-methylcytosine (Ehrlich et al. 1982, reviewed in Klose and Bird 2006, Ooi et al. 2009, Moore et al. 2013). Methylation of DNA occurs at cytosines that are mainly located in CG dinucleotides. CG dinucleotides are unevenly distributed in the genome. Promoter regions tend to have a high CG-content, forming so-called CG-islands (CGIs), while the CG-content in the remaining part of the genome is much lower. CGIs tend to be unmethylated, while the majority of CGs outside CGIs are methylated. Methylation in promoters and first exons tends to repress transcription while methylation in gene bodies (regions of genes downstream of the promoter and first exon) correlates with transcription (reviewed in Ehrlich and Lacey 2013, Kulis et al. 2013). Proteins such as MeCP2 and MBDs specifically bind 5-methylcytosine and may recruit other factors.
Mammalian development has two major episodes of genome-wide demethylation and remethylation (reviewed in Zhou 2012, Guibert and Weber 2013, Hackett and Surani 2013, Dean 2014). In mice about 1 day after fertilization the paternal genome is actively demethylated by TET proteins together with thymine DNA glycosylase and the maternal genome is demethylated by passive dilution during replication, however methylation at imprinted sites is maintained. The genome has its lowest methylation level about 3.5 days post-fertilization. Remethylation occurs by 6.5 days post-fertilization. The second demethylation-remethylation event occurs in primordial germ cells of the developing embryo about 12.5 days post-fertilization. DNMT3A and DNMT3B, together with the non-catalytic DNMT3L, play major roles in the remethylation events (reviewed in Chen and Chan 2014). How the methyltransferases are directed to particular regions of the genome remains an area of active research. The mechanisms at each locus may differ in detail but a connection between histone modifications and DNA methylation has been observed (reviewed in Rose and Klose 2014).
Epigenetic processes regulate gene expression by modulating the frequency, rate, or extent of gene expression in a mitotically or meiotically heritable way that does not entail a change in the DNA sequence. Originally the definition applied only to heritability across generations but later also encompassed the heritable changes that occur during cellular differentiation within one organism.
Molecular analysis shows epigenetic changes comprise covalent modifications, such as methylation and acetylation, to DNA and histones. RNA interference has been implicated in the initiation of some epigenetic changes, for example transcriptional silencing of transposons. Proteins which bind to the modified DNA and histones are then responsible for repressing transcription and for maintaining the epigenetic modifications during cell division.
During differentiation, patterns of gene expression are established by polycomb complexes PRC1 and PRC2. PRC2 methylates histones and DNA to produce the initial marks of repression: trimethylated lysine-27 on histone H3 (H3K27me3) and 5-methylcytosine in DNA. PRC2, through its component EZH2 or, in some complexes, EZH1 trimethylates lysine-27 of histone H3. The H3K27me3 produced by PRC2 is bound by the Polycomb subunit of PRC1. PRC1 ubiquitinates histone H2A and maintains repression.
PRC2 and other epigenetic systems modulate gene expression through DNA methyation, the transfer of a methyl group from S-adenosylmethionine to the 5 position of cytosine in DNA by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3A, and DNMT3B.
In the reverse process TET1,2,3 and TDG demethylate DNA through the oxidation of the methyl group of 5-methylcytosine by TET enzymes and the excision of the oxidized product (5-formylcytosine or 5-carboxylcytosine) by TDG.
Ribosomal RNA (rRNA) genes are activated and deactivated according to the metabolic requirements of the cell. Positive epigenetic regulation of rRNA expression occurs through chromatin modifications produced by activators such as ERCC6 (CSB), the B-WICH complex, and histone acetylases such as KAT2B (PCAF). Negative epigenetic regulation of rRNA expression occurs through chromatin modifications produced by repressors such as the eNoSC complex, SIRT1, and the NoRC complex.
WDR5 is a component of six histone methyltransferases and three histone acetyltransferases involved in epigenetic regulation of gene expression (reviewed in Guarnaccia and Tansey 2018).
Molecular analysis shows epigenetic changes comprise covalent modifications, such as methylation and acetylation, to DNA and histones. RNA interference has been implicated in the initiation of some epigenetic changes, for example transcriptional silencing of transposons. Proteins which bind to the modified DNA and histones are then responsible for repressing transcription and for maintaining the epigenetic modifications during cell division.
During differentiation, patterns of gene expression are established by polycomb complexes PRC1 and PRC2. PRC2 methylates histones and DNA to produce the initial marks of repression: trimethylated lysine-27 on histone H3 (H3K27me3) and 5-methylcytosine in DNA. PRC2, through its component EZH2 or, in some complexes, EZH1 trimethylates lysine-27 of histone H3. The H3K27me3 produced by PRC2 is bound by the Polycomb subunit of PRC1. PRC1 ubiquitinates histone H2A and maintains repression.
PRC2 and other epigenetic systems modulate gene expression through DNA methyation, the transfer of a methyl group from S-adenosylmethionine to the 5 position of cytosine in DNA by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3A, and DNMT3B.
In the reverse process TET1,2,3 and TDG demethylate DNA through the oxidation of the methyl group of 5-methylcytosine by TET enzymes and the excision of the oxidized product (5-formylcytosine or 5-carboxylcytosine) by TDG.
Ribosomal RNA (rRNA) genes are activated and deactivated according to the metabolic requirements of the cell. Positive epigenetic regulation of rRNA expression occurs through chromatin modifications produced by activators such as ERCC6 (CSB), the B-WICH complex, and histone acetylases such as KAT2B (PCAF). Negative epigenetic regulation of rRNA expression occurs through chromatin modifications produced by repressors such as the eNoSC complex, SIRT1, and the NoRC complex.
WDR5 is a component of six histone methyltransferases and three histone acetyltransferases involved in epigenetic regulation of gene expression (reviewed in Guarnaccia and Tansey 2018).
Gene expression encompasses transcription and translation and the regulation of these processes. RNA Polymerase I Transcription produces the large preribosomal RNA transcript (45S pre-rRNA) that is processed to yield 18S rRNA, 28S rRNA, and 5.8S rRNA, accounting for about half the RNA in a cell. RNA Polymerase II transcription produces messenger RNAs (mRNA) as well as a subset of non-coding RNAs including many small nucleolar RNAs (snRNA) and microRNAs (miRNA). RNA Polymerase III Transcription produces transfer RNAs (tRNA), 5S RNA, 7SL RNA, and U6 snRNA. Transcription from mitochondrial promoters is performed by the mitochondrial RNA polymerase, POLRMT, to yield long transcripts from each DNA strand that are processed to yield 12S rRNA, 16S rRNA, tRNAs, and a few RNAs encoding components of the electron transport chain. Regulation of gene expression can be divided into epigenetic regulation, transcriptional regulation, and post-transcription regulation (comprising translational efficiency and RNA stability). Epigenetic regulation of gene expression is the result of heritable chemical modifications to DNA and DNA-binding proteins such as histones. Epigenetic changes result in altered chromatin complexes that influence transcription. Gene Silencing by RNA mostly occurs post-transcriptionally but can also affect transcription. Small RNAs originating from the genome (miRNAs) or from exogenous RNA (siRNAs) are processed and transferred to the RNA-induced silencing complex (RISC), which interacts with complementary RNA to cause cleavage, translational inhibition, or transcriptional inhibition.