Functions of DNA Methylation: Islands, Start Sites, Gene Bodies and Beyond

Overview

Journal Nat Rev Genet

Specialty Genetics

Date 2012 May 30

PMID 22641018

Citations 2884

Authors

Peter A Jones

Affiliations

Soon will be listed here.

Abstract

DNA methylation is frequently described as a 'silencing' epigenetic mark, and indeed this function of 5-methylcytosine was originally proposed in the 1970s. Now, thanks to improved genome-scale mapping of methylation, we can evaluate DNA methylation in different genomic contexts: transcriptional start sites with or without CpG islands, in gene bodies, at regulatory elements and at repeat sequences. The emerging picture is that the function of DNA methylation seems to vary with context, and the relationship between DNA methylation and transcription is more nuanced than we realized at first. Improving our understanding of the functions of DNA methylation is necessary for interpreting changes in this mark that are observed in diseases such as cancer.

Citing Articles

DNA Methylation-Regulated ZDHHC13 Promotes the Progression of Parkinson's Disease.

Liao J, Bei L, Nie P, Liu P, Zhang Y Mol Neurobiol. 2025; .

PMID: 40088380 DOI: 10.1007/s12035-025-04829-1.

Blood-Based DNA Methylation Biomarkers to Identify Risk and Progression of Cardiovascular Disease.

Willmer T, Mabasa L, Sharma J, Muller C, Johnson R Int J Mol Sci. 2025; 26(5).

PMID: 40076974 PMC: 11900213. DOI: 10.3390/ijms26052355.

Analysis of the Transcriptional Control of in Chicken: IRF1 and GATA1 as Negative Regulators.

Qiu L, Wang H, Li W, Yang T, Bai H, Chang G Animals (Basel). 2025; 15(5).

PMID: 40075948 PMC: 11898421. DOI: 10.3390/ani15050665.

Green forage impacts on the DNA methylation in the ruminal wall of Italian mediterranean dairy buffaloes.

Fioriniello S, Salzano A, Bifulco G, Aiese Cigliano R, Della Ragione F, Campanile G Sci Rep. 2025; 15(1):8074.

PMID: 40057542 PMC: 11890600. DOI: 10.1038/s41598-025-91969-y.

Detection of Novel hub-methylated differentially expressed genes in pregnant women with gestational diabetes mellitus via WGCNA of epigenome-wide and transcriptome-wide profiling.

Hamdan H Int J Health Sci (Qassim). 2025; 19(2):4-16.

PMID: 40046791 PMC: 11877056.

References

Challen G, Sun D, Jeong M, Luo M, Jelinek J, Berg J . Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet. 2011; 44(1):23-31. PMC: 3637952. DOI: 10.1038/ng.1009. View

Xu G, Bestor T, Bourchis D, Hsieh C, Tommerup N, Bugge M . Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 2000; 402(6758):187-91. DOI: 10.1038/46052. View

Widschwendter M, Fiegl H, Egle D, Mueller-Holzner E, Spizzo G, Marth C . Epigenetic stem cell signature in cancer. Nat Genet. 2007; 39(2):157-8. DOI: 10.1038/ng1941. View

Cooper D, Youssoufian H . The CpG dinucleotide and human genetic disease. Hum Genet. 1988; 78(2):151-5. DOI: 10.1007/BF00278187. View

Wu H, Zhang Y . Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev. 2011; 25(23):2436-52. PMC: 3243055. DOI: 10.1101/gad.179184.111. View

Baylin S, Jones P . A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011; 11(10):726-34. PMC: 3307543. DOI: 10.1038/nrc3130. View

Ong C, Corces V . Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet. 2011; 12(4):283-93. PMC: 3175006. DOI: 10.1038/nrg2957. View

Jones P, Wolkowicz M, Rideout 3rd W, Gonzales F, Marziasz C, Coetzee G . De novo methylation of the MyoD1 CpG island during the establishment of immortal cell lines. Proc Natl Acad Sci U S A. 1990; 87(16):6117-21. PMC: 54483. DOI: 10.1073/pnas.87.16.6117. View

Cortazar D, Kunz C, Selfridge J, Lettieri T, Saito Y, MacDougall E . Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature. 2011; 470(7334):419-23. DOI: 10.1038/nature09672. View

10.

Rideout 3rd W, Coetzee G, Olumi A, Jones P . 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes. Science. 1990; 249(4974):1288-90. DOI: 10.1126/science.1697983. View

11.

Thomson J, Skene P, Selfridge J, Clouaire T, Guy J, Webb S . CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature. 2010; 464(7291):1082-6. PMC: 3730110. DOI: 10.1038/nature08924. View

12.

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

13.

Yoder J, Walsh C, Bestor T . Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 1997; 13(8):335-40. DOI: 10.1016/s0168-9525(97)01181-5. View

14.

Branco M, Ficz G, Reik W . Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet. 2011; 13(1):7-13. DOI: 10.1038/nrg3080. View

15.

Gu T, Guo F, Yang H, Wu H, Xu G, Liu W . The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature. 2011; 477(7366):606-10. DOI: 10.1038/nature10443. View

16.

Riggs A . X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet. 1975; 14(1):9-25. DOI: 10.1159/000130315. View

17.

Markl I, Cheng J, Liang G, Shibata D, Laird P, Jones P . Global and gene-specific epigenetic patterns in human bladder cancer genomes are relatively stable in vivo and in vitro over time. Cancer Res. 2001; 61(15):5875-84. View

18.

Nili Gal-Yam E, Jeong S, Tanay A, Egger G, Lee A, Jones P . Constitutive nucleosome depletion and ordered factor assembly at the GRP78 promoter revealed by single molecule footprinting. PLoS Genet. 2006; 2(9):e160. PMC: 1574359. DOI: 10.1371/journal.pgen.0020160. View

19.

Harrington M, Jones P, Imagawa M, Karin M . Cytosine methylation does not affect binding of transcription factor Sp1. Proc Natl Acad Sci U S A. 1988; 85(7):2066-70. PMC: 279929. DOI: 10.1073/pnas.85.7.2066. View

20.

Szulwach K, Li X, Li Y, Song C, Han J, Kim S . Integrating 5-hydroxymethylcytosine into the epigenomic landscape of human embryonic stem cells. PLoS Genet. 2011; 7(6):e1002154. PMC: 3121778. DOI: 10.1371/journal.pgen.1002154. View