DNA methylation (Homo sapiens)

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9, 10, 13, 15, 17...4, 14, 16, 20, 342, 3, 6, 8, 19...6, 21, 304, 14, 33, 40, 411, 5, 6, 26, 397, 11, 14, 16, 23...12, 14, 33, 41nucleoplasmHIST1H3A HIST1H3A H3F3A HIST1H4 DNMT3A:DNMT3L:ChromatinHIST1H3A DNMT3A HIST2H3A UHRF1 HIST1H3A DNMT3L DNMT1 DNMT3L HIST2H3A DNMT1 UHRF1 AdoMetHIST1H4 UHRF1:Chromatin withhemimethylCAdoHcyH3F3A DNMT1:UHRF1:Chromatin with symmetric methylCDNMT3L DNMT3A:DNMT3L:Chromatin with 5mCDNMT3A:DNMT3LHIST1H4 HIST2H3A DNMT3B:DNMT3LHIST1H4 Chromatin withhemimethylCHIST2H3A UHRF1AdoHcyDNMT3A HIST2H3A DNMT3B:DNMT3L:ChromatinHIST1H4 ChromatinHIST1H3A DNMT3A DNMT3L H3F3A HIST1H4 HIST2H3A DNMT1HIST1H3A H3F3A HIST1H4 DNMT3B DNMT3B:DNMT3L:Chromatin with 5mCHIST1H3A DNMT3L DNMT3B DNMT3L HIST1H4 HIST2H3A H3F3A HIST1H4 DNMT1:UHRF1:Chromatin with hemimethylCUHRF1 H3F3A HIST1H3A DNMT3B H3F3A HIST2H3A H3F3A AdoMetHIST1H3A H3F3A HIST2H3A 4, 1414, 16, 34


Description

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). Source:Reactome.

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Bibliography

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History

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114800view16:29, 25 January 2021ReactomeTeamReactome version 75
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99998view16:19, 31 October 2018ReactomeTeamreactome version 63
99552view14:53, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99184view12:42, 31 October 2018ReactomeTeamreactome version 62
93926view13:45, 16 August 2017ReactomeTeamreactome version 61
93512view11:25, 9 August 2017ReactomeTeamreactome version 61
87433view13:33, 22 July 2016MkutmonOntology Term : 'pathway pertinent to DNA replication and repair, cell cycle, maintenance of genomic integrity, RNA and protein biosynthesis' added !
86607view09:22, 11 July 2016ReactomeTeamreactome version 56
83348view10:55, 18 November 2015ReactomeTeamVersion54
81507view13:02, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
Chromatin with hemimethylCComplexR-HSA-5334149 (Reactome)
ChromatinComplexR-HSA-3211736 (Reactome)
DNMT1 ProteinP26358 (Uniprot-TrEMBL)
DNMT1:UHRF1:Chromatin with hemimethylCComplexR-HSA-5334113 (Reactome)
DNMT1:UHRF1:Chromatin with symmetric methylCComplexR-HSA-5334142 (Reactome)
DNMT1ProteinP26358 (Uniprot-TrEMBL)
DNMT3A ProteinQ9Y6K1 (Uniprot-TrEMBL)
DNMT3A:DNMT3L:Chromatin with 5mCComplexR-HSA-5334119 (Reactome)
DNMT3A:DNMT3L:ChromatinComplexR-HSA-5334159 (Reactome)
DNMT3A:DNMT3LComplexR-HSA-5334143 (Reactome)
DNMT3B ProteinQ9UBC3 (Uniprot-TrEMBL)
DNMT3B:DNMT3L:Chromatin with 5mCComplexR-HSA-5334110 (Reactome)
DNMT3B:DNMT3L:ChromatinComplexR-HSA-5334124 (Reactome)
DNMT3B:DNMT3LComplexR-HSA-5334136 (Reactome)
DNMT3L ProteinQ9UJW3 (Uniprot-TrEMBL)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
UHRF1 ProteinQ96T88 (Uniprot-TrEMBL)
UHRF1:Chromatin with hemimethylCComplexR-HSA-5334140 (Reactome)
UHRF1ProteinQ96T88 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
AdoHcyArrowR-HSA-5334097 (Reactome)
AdoHcyArrowR-HSA-5334151 (Reactome)
AdoHcyArrowR-HSA-5334152 (Reactome)
AdoMetR-HSA-5334097 (Reactome)
AdoMetR-HSA-5334151 (Reactome)
AdoMetR-HSA-5334152 (Reactome)
Chromatin with hemimethylCR-HSA-5334099 (Reactome)
ChromatinR-HSA-5334164 (Reactome)
ChromatinR-HSA-5334179 (Reactome)
DNMT1:UHRF1:Chromatin with hemimethylCArrowR-HSA-5334160 (Reactome)
DNMT1:UHRF1:Chromatin with hemimethylCR-HSA-5334151 (Reactome)
DNMT1:UHRF1:Chromatin with hemimethylCmim-catalysisR-HSA-5334151 (Reactome)
DNMT1:UHRF1:Chromatin with symmetric methylCArrowR-HSA-5334151 (Reactome)
DNMT1R-HSA-5334160 (Reactome)
DNMT3A:DNMT3L:Chromatin with 5mCArrowR-HSA-5334152 (Reactome)
DNMT3A:DNMT3L:ChromatinArrowR-HSA-5334179 (Reactome)
DNMT3A:DNMT3L:ChromatinR-HSA-5334152 (Reactome)
DNMT3A:DNMT3L:Chromatinmim-catalysisR-HSA-5334152 (Reactome)
DNMT3A:DNMT3LR-HSA-5334179 (Reactome)
DNMT3B:DNMT3L:Chromatin with 5mCArrowR-HSA-5334097 (Reactome)
DNMT3B:DNMT3L:ChromatinArrowR-HSA-5334164 (Reactome)
DNMT3B:DNMT3L:ChromatinR-HSA-5334097 (Reactome)
DNMT3B:DNMT3L:Chromatinmim-catalysisR-HSA-5334097 (Reactome)
DNMT3B:DNMT3LR-HSA-5334164 (Reactome)
R-HSA-5334097 (Reactome) DNMT3B methylates the 5 position of cytosine in DNA. DNMT3B preferentially methylates cytosine residues that have T at the -1 position and G at the +1 position (Wienholz et al. 2010). Sites methylated de novo by DNMT3B tend to be in transcriptionally inactive regions associated with histone H3 trimethylated at lysine-27 (Choi et al. 2011). Association with DNMT3L increases the processivity of DNMT3B (Van Emburgh and Robertson 2011) and increases methylation at sites that would have low methylation by the activity of DNMT3B alone (Wienholz et al. 2010). Interaction of DNMT3L with DNMT3B-isoform2 stimulates methylation activity significantly (Van Emburgh and Robertson 2011), but interaction of DNMT3L with DNMT3B-isoform1 has little effect on methylation activity (Chedin et al. 2002, Van Emburgh and Robertson 2011). Methylation in embryos but not in gametes (oocytes and spermatozoa) requires DNMT3B (Okano et al. 1999, Kaneda et al. 2004, Borgel et al. 2010, Kaneda et al. 2010).
R-HSA-5334099 (Reactome) UHRF1 (also known as Np95) preferentially binds hemimethylated CG dinucleotides in DNA via its SRA domain (Avvakumov et al. 2008, Qian et al. 2008, and inferred from the mouse homolog). The UHRF1-bound unmethylated cytosine base is flipped out of the DNA helix and into a pocket of UHRF1 (Avvakumov et al. 2008). UHRF1 also binds dimethylated and trimethylated lysine-9 of histone H3 through its tandem Tudor domain (Nady et al. 2011, Rothbart et al. 2012, Rothbart et al. 2013, Cheng et al. 2013) and unmethylated histone H3 through its PHD domain (Hu et al. 2011, Wang et al. 2011, Rajakumara et al. 2011, Cheng et al. 2013).
R-HSA-5334151 (Reactome) DNMT1 transfers a methyl group from S-adenosylmethionine to the 5-position of the cytosine ring of cytosine residues in DNA. Purified human DNMT1 shows a 7 to 21-fold preference for hemimethylated CG motifs in DNA compared to unmethylated CG motifs (Pradhan et al. 1999) thus DNMT1 tends to maintain existing methylation through DNA replication. The binding of the CXXC motif of DNMT1 to cytosine in symmetrically unmethylated CG dinucleotides prevents access of cytosine to the active site and thereby prevents de novo methylation (Song et al. 2011). UHRF1 binds hemimethylated DNA and histone H3 tails methylated at lysine-9 and recruits DNMT1 to methylate hemimethylated DNA (Bostick et al. 2007, reviewed in Ooi and Bestor 2008). Interaction of UHRF1 with DNMT1 increases the methylation activity of DNMT1 about 5-fold (Bashtrykov et al. 2014).
R-HSA-5334152 (Reactome) DNMT3A methylates the 5 position of cytosine in DNA. As inferred from the mouse homolog, DNMT3A generates asymmetric methylation (methylation of only one strand) of CG dinucleotides and non-CG cytosine residues. DNMT3L interacts with and stimulates the catalytic activity of DNMT3A2 and DNMT3A (Chen et al. 2005, Kareta et al. 2006, Ooi et al. 2007, Holz-Schietinger and Reich 2010). DNMT3A preferentially methylates DNA in regions of transcriptionally active chromatin: DNMT3A-isoform1 transfected into human cells (293T cells) tended to methylate active regions of the genome that were associated with trimethylated lysine-4 of histone H3 (H4K4me3) (Choi et al. 2011). Likewise, in mouse oocytes and embryos CG islands methylated by DNMT3A tend to be located in active transcription units, but with low levels of methylated H3K4 (Smallwood et al. 2011). DNMT3A and its homologue DNMT3B have different preferences for flanking sequences of CG dinucleotides, with DNMT3A tending to methylate sites that have T at the -2 position and C at the +2 position (Wienholz et al. 2010). DNMT3L increases methylation by DNMT3A at sites that are weakly methylated by DNMT3A alone (Wienholz et al. 2010).
R-HSA-5334160 (Reactome) As inferred from the mouse homolog, UHRF1 associates with hemimethylated DNA and histone H3 tails methylated at lysine-9. UHRF1 recruits and tethers DNMT1 (Bostick et al. 2007). The association of UHRF1 with DNMT1 occurs preferentially during S-phase when DNA is hemimethylated as the newly replicated strand remains transiently unmethylated (Zhang et al. 2011, Hervouet et al. 2012). DNMT1 also forms complexes with transcription factors such as TP53 (p53) and YY1 at other times during the cell cycle (Hervouet et al. 2012).
R-HSA-5334164 (Reactome) The C-terminal region of DNMT3L associates with C-terminal regions of DNMT3B-isoform1 and DNMT3B-isoform2 (Chen et al. 2005, Van Emburgh and Robertson 2011, human DNMT3L with mouse Dnmt3b in Suetake et al. 2004). DNMT3L binds the unmethylated N-terminus of histone H3 (Ooi et al. 2007), leading DNMT3L to target DNMT3B to chromatin (Wienholz et al. 2010). As inferred from mouse homologs, DNMT3B also binds the unmodified N-terminus of histone H3.
R-HSA-5334179 (Reactome) DNMT3L is a non-catalytic homologue of DNMT3A and DNMT3B which binds unmethylated lysine-4 of histone H3 (H3K4, Ooi et al. 2007) and recruits DNMT3A-isoform2 (germ cell specific) (Chen et al. 2005, Kareta et al. 2006, Ooi et al. 2007) and, to a lesser extent, other isoforms of DNMT3A via an interaction between the C-terminal regions of DNMT3L and DNMT3A (Chen et al. 2005). Furthermore, DNMT3A binds unmodified tails of histone H3 (Otani et al. 2009). DNMT3L and DNMT3A form tetramers (DNMT3L:DNMT3A:DNMT3A:DNMT3L) that bind DNA located in euchromatic regions (Holz-Schietinger et al. 2011, also inferred from mouse). DNMT3A without DNMT3L forms oligomers that are located in heterochromatin.
UHRF1:Chromatin with hemimethylCArrowR-HSA-5334099 (Reactome)
UHRF1:Chromatin with hemimethylCR-HSA-5334160 (Reactome)
UHRF1R-HSA-5334099 (Reactome)
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