The Interplay Between DNA and Histone Methylation: Molecular Mechanisms and Disease Implications

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2021 Apr 12

PMID 33844406

Citations 74

Authors

Yinglu Li

Xiao Chen

Chao Lu

Affiliations

Soon will be listed here.

Abstract

Methylation of cytosine in CpG dinucleotides and histone lysine and arginine residues is a chromatin modification that critically contributes to the regulation of genome integrity, replication, and accessibility. A strong correlation exists between the genome-wide distribution of DNA and histone methylation, suggesting an intimate relationship between these epigenetic marks. Indeed, accumulating literature reveals complex mechanisms underlying the molecular crosstalk between DNA and histone methylation. These in vitro and in vivo discoveries are further supported by the finding that genes encoding DNA- and histone-modifying enzymes are often mutated in overlapping human diseases. Here, we summarize recent advances in understanding how DNA and histone methylation cooperate to maintain the cellular epigenomic landscape. We will also discuss the potential implication of these insights for understanding the etiology of, and developing biomarkers and therapies for, human congenital disorders and cancers that are driven by chromatin abnormalities.

Citing Articles

Design, synthesis and evaluation of pyrimidinobenzylamide and pyrimidinothiophenamide derivatives as inhibitors of DOT1L and related epigenetic targets DNMT3a, PRMT4 and other HMTs.

Castillo-Aguilera O, Depreux P, Halby L, Bailly C, Dominguez-Ramirez L, Gul S RSC Med Chem. 2025; .

PMID: 40061000 PMC: 11886420. DOI: 10.1039/d4md00899e.

The Malignant Transformation of Viral Hepatitis to Hepatocellular Carcinoma: Mechanisms and Interventions.

Yuan H, Xu R, Li S, Zheng M, Tong Q, Xiang M MedComm (2020). 2025; 6(3):e70121.

PMID: 40060195 PMC: 11890166. DOI: 10.1002/mco2.70121.

Bridging epigenomics and tumor immunometabolism: molecular mechanisms and therapeutic implications.

Xie X, Liu W, Yuan Z, Chen H, Mao W Mol Cancer. 2025; 24(1):71.

PMID: 40057791 PMC: 11889836. DOI: 10.1186/s12943-025-02269-y.

SIRT1/DNMT3B-mediated epigenetic gene silencing in response to phytoestrogens in mammary epithelial cells.

Ma Y, Boycott C, Zhang J, Gomilar R, Yang T, Stefanska B Epigenetics. 2025; 20(1):2473770.

PMID: 40029260 PMC: 11881848. DOI: 10.1080/15592294.2025.2473770.

New perspectives on DNA methylation modifications in ocular diseases.

Zong F, Jia D, Huang G, Pan M, Hu H, Song S Int J Ophthalmol. 2025; 18(2):340-350.

PMID: 39967986 PMC: 11754021. DOI: 10.18240/ijo.2025.02.19.

References

Veland N, Hardikar S, Zhong Y, Gayatri S, Dan J, Strahl B . The Arginine Methyltransferase PRMT6 Regulates DNA Methylation and Contributes to Global DNA Hypomethylation in Cancer. Cell Rep. 2017; 21(12):3390-3397. PMC: 5753604. DOI: 10.1016/j.celrep.2017.11.082. View

Heyn P, Logan C, Fluteau A, Challis R, Auchynnikava T, Martin C . Gain-of-function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions. Nat Genet. 2018; 51(1):96-105. PMC: 6520989. DOI: 10.1038/s41588-018-0274-x. View

Myant K, Termanis A, Sundaram A, Boe T, Li C, Merusi C . LSH and G9a/GLP complex are required for developmentally programmed DNA methylation. Genome Res. 2010; 21(1):83-94. PMC: 3012929. DOI: 10.1101/gr.108498.110. View

Hansen R, Wijmenga C, Luo P, Stanek A, Canfield T, Weemaes C . The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A. 1999; 96(25):14412-7. PMC: 24450. DOI: 10.1073/pnas.96.25.14412. View

Zhang Y, Charlton J, Karnik R, Beerman I, Smith Z, Gu H . Targets and genomic constraints of ectopic Dnmt3b expression. Elife. 2018; 7. PMC: 6251628. DOI: 10.7554/eLife.40757. View

Klein C, Botuyan M, Wu Y, Ward C, Nicholson G, Hammans S . Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat Genet. 2011; 43(6):595-600. PMC: 3102765. DOI: 10.1038/ng.830. View

Vaughan R, Dickson B, Whelihan M, Johnstone A, Cornett E, Cheek M . Chromatin structure and its chemical modifications regulate the ubiquitin ligase substrate selectivity of UHRF1. Proc Natl Acad Sci U S A. 2018; 115(35):8775-8780. PMC: 6126761. DOI: 10.1073/pnas.1806373115. View

Bottcher J, Dilworth D, Reiser U, Neumuller R, Schleicher M, Petronczki M . Fragment-based discovery of a chemical probe for the PWWP1 domain of NSD3. Nat Chem Biol. 2019; 15(8):822-829. DOI: 10.1038/s41589-019-0310-x. View

Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M . Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009; 114(1):144-7. PMC: 2710942. DOI: 10.1182/blood-2009-03-210039. View

10.

Aref-Eshghi E, Schenkel L, Lin H, Skinner C, Ainsworth P, Pare G . The defining DNA methylation signature of Kabuki syndrome enables functional assessment of genetic variants of unknown clinical significance. Epigenetics. 2017; 12(11):923-933. PMC: 5788422. DOI: 10.1080/15592294.2017.1381807. View

11.

Douglas J, Hanks S, Temple I, Davies S, Murray A, Upadhyaya M . NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. Am J Hum Genet. 2002; 72(1):132-43. PMC: 378618. DOI: 10.1086/345647. View

12.

Weisenberger D, Velicescu M, Cheng J, Gonzales F, Liang G, Jones P . Role of the DNA methyltransferase variant DNMT3b3 in DNA methylation. Mol Cancer Res. 2004; 2(1):62-72. View

13.

Weemaes C, Van Tol M, Wang J, van Ostaijen-Ten Dam M, van Eggermond M, Thijssen P . Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects. Eur J Hum Genet. 2013; 21(11):1219-25. PMC: 3798845. DOI: 10.1038/ejhg.2013.40. View

14.

Deblois G, Madani Tonekaboni S, Grillo G, Martinez C, Kao Y, Tai F . Epigenetic Switch-Induced Viral Mimicry Evasion in Chemotherapy-Resistant Breast Cancer. Cancer Discov. 2020; 10(9):1312-1329. DOI: 10.1158/2159-8290.CD-19-1493. View

15.

Carrozza M, Li B, Florens L, Suganuma T, Swanson S, Lee K . Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell. 2005; 123(4):581-92. DOI: 10.1016/j.cell.2005.10.023. View

16.

Jones P, Liang G . Rethinking how DNA methylation patterns are maintained. Nat Rev Genet. 2009; 10(11):805-11. PMC: 2848124. DOI: 10.1038/nrg2651. View

17.

Bayliss J, Mukherjee P, Lu C, Jain S, Chung C, Martinez D . Lowered H3K27me3 and DNA hypomethylation define poorly prognostic pediatric posterior fossa ependymomas. Sci Transl Med. 2016; 8(366):366ra161. PMC: 5123566. DOI: 10.1126/scitranslmed.aah6904. View

18.

Kong X, Chen J, Xie W, Brown S, Cai Y, Wu K . Defining UHRF1 Domains that Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties. Cancer Cell. 2019; 35(4):633-648.e7. PMC: 6521721. DOI: 10.1016/j.ccell.2019.03.003. View

19.

Sharif J, Muto M, Takebayashi S, Suetake I, Iwamatsu A, Endo T . The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007; 450(7171):908-12. DOI: 10.1038/nature06397. View

20.

Auclair G, Borgel J, Sanz L, Vallet J, Guibert S, Dumas M . EHMT2 directs DNA methylation for efficient gene silencing in mouse embryos. Genome Res. 2015; 26(2):192-202. PMC: 4728372. DOI: 10.1101/gr.198291.115. View