Transcription Factors As Readers and Effectors of DNA Methylation

Overview

Journal Nat Rev Genet

Specialty Genetics

Date 2016 Aug 2

PMID 27479905

Citations 322

Authors

Heng Zhu

Guohua Wang

Jiang Qian

Affiliations

Soon will be listed here.

Abstract

Recent technological advances have made it possible to decode DNA methylomes at single-base-pair resolution under various physiological conditions. Many aberrant or differentially methylated sites have been discovered, but the mechanisms by which changes in DNA methylation lead to observed phenotypes, such as cancer, remain elusive. The classical view of methylation-mediated protein-DNA interactions is that only proteins with a methyl-CpG binding domain (MBD) can interact with methylated DNA. However, evidence is emerging to suggest that transcription factors lacking a MBD can also interact with methylated DNA. The identification of these proteins and the elucidation of their characteristics and the biological consequences of methylation-dependent transcription factor-DNA interactions are important stepping stones towards a mechanistic understanding of methylation-mediated biological processes, which have crucial implications for human development and disease.

Citing Articles

Dietary polyunsaturated fatty acids affect PPARγ promoter methylation status and regulate the PPARγ/COX2 pathway in some colorectal cancer cell lines.

Babaeenezhad E, Khosravi P, Moradi Sarabi M Genes Nutr. 2025; 20(1):2.

PMID: 40038577 PMC: 11877738. DOI: 10.1186/s12263-025-00764-x.

Prenatal maternal life adversity impacts on learning and memory in offspring: implication to transgenerational epigenetic inheritance.

Adeline Dorothy P, Rajan K Front Neurosci. 2025; 19:1518046.

PMID: 40018363 PMC: 11865043. DOI: 10.3389/fnins.2025.1518046.

The epigenetic landscape of brain metastasis.

Powell A, Watson L, Luzietti L, Prekovic S, Young L, Vareslija D Oncogene. 2025; .

PMID: 40016470 DOI: 10.1038/s41388-025-03315-1.

Interaction of genetic variants and methylation in transcript-level expression regulation in Alzheimer's disease by multi-omics data analysis.

Han S, Cho S, Choi W, Eilbeck K, Coon H, Nho K BMC Genomics. 2025; 26(1):170.

PMID: 39979805 PMC: 11844006. DOI: 10.1186/s12864-025-11362-x.

Interplay between pioneer transcription factors and epigenetic modifiers in cell reprogramming.

Mirizio G, Sampson S, Iwafuchi M Regen Ther. 2025; 28():246-252.

PMID: 39834592 PMC: 11745816. DOI: 10.1016/j.reth.2024.12.014.

References

Krebs A, Dessus-Babus S, Burger L, Schubeler D . High-throughput engineering of a mammalian genome reveals building principles of methylation states at CG rich regions. Elife. 2014; 3:e04094. PMC: 4381937. DOI: 10.7554/eLife.04094. View

Yu D, Ware C, Waterland R, Zhang J, Chen M, Gadkari M . Developmentally programmed 3' CpG island methylation confers tissue- and cell-type-specific transcriptional activation. Mol Cell Biol. 2013; 33(9):1845-58. PMC: 3624169. DOI: 10.1128/MCB.01124-12. View

Liu Y, Toh H, Sasaki H, Zhang X, Cheng X . An atomic model of Zfp57 recognition of CpG methylation within a specific DNA sequence. Genes Dev. 2012; 26(21):2374-9. PMC: 3489995. DOI: 10.1101/gad.202200.112. View

Baylin S . DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol. 2005; 2 Suppl 1:S4-11. DOI: 10.1038/ncponc0354. View

Kinde B, Gabel H, Gilbert C, Griffith E, Greenberg M . Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2. Proc Natl Acad Sci U S A. 2015; 112(22):6800-6. PMC: 4460470. DOI: 10.1073/pnas.1411269112. View

Springer N, Kaeppler S . Evolutionary divergence of monocot and dicot methyl-CpG-binding domain proteins. Plant Physiol. 2005; 138(1):92-104. PMC: 1104165. DOI: 10.1104/pp.105.060566. View

Khrapunov S, Warren C, Cheng H, Berko E, Greally J, Brenowitz M . Unusual characteristics of the DNA binding domain of epigenetic regulatory protein MeCP2 determine its binding specificity. Biochemistry. 2014; 53(21):3379-91. PMC: 4045320. DOI: 10.1021/bi500424z. View

Stadler M, Murr R, Burger L, Ivanek R, Lienert F, Scholer A . DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011; 480(7378):490-5. DOI: 10.1038/nature10716. View

Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim S . Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011; 19(1):17-30. PMC: 3229304. DOI: 10.1016/j.ccr.2010.12.014. View

10.

Iwafuchi-Doi M, Zaret K . Pioneer transcription factors in cell reprogramming. Genes Dev. 2014; 28(24):2679-92. PMC: 4265672. DOI: 10.1101/gad.253443.114. View

11.

Buganim Y, Faddah D, Jaenisch R . Mechanisms and models of somatic cell reprogramming. Nat Rev Genet. 2013; 14(6):427-39. PMC: 4060150. DOI: 10.1038/nrg3473. View

12.

Schoenherr C, Levorse J, Tilghman S . CTCF maintains differential methylation at the Igf2/H19 locus. Nat Genet. 2002; 33(1):66-9. DOI: 10.1038/ng1057. View

13.

Wu H, Wu X, Shen L, Zhang Y . Single-base resolution analysis of active DNA demethylation using methylase-assisted bisulfite sequencing. Nat Biotechnol. 2014; 32(12):1231-40. PMC: 4269366. DOI: 10.1038/nbt.3073. View

14.

Robertson K . DNA methylation and human disease. Nat Rev Genet. 2005; 6(8):597-610. DOI: 10.1038/nrg1655. View

15.

Tate P, Bird A . Effects of DNA methylation on DNA-binding proteins and gene expression. Curr Opin Genet Dev. 1993; 3(2):226-31. DOI: 10.1016/0959-437x(93)90027-m. View

16.

Prokhortchouk A, Hendrich B, Jorgensen H, Ruzov A, Wilm M, Georgiev G . The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev. 2001; 15(13):1613-8. PMC: 312733. DOI: 10.1101/gad.198501. View

17.

He Y, Li B, Li Z, Liu P, Wang Y, Tang Q . Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011; 333(6047):1303-7. PMC: 3462231. DOI: 10.1126/science.1210944. View

18.

Feng S, Cokus S, Zhang X, Chen P, Bostick M, Goll M . Conservation and divergence of methylation patterning in plants and animals. Proc Natl Acad Sci U S A. 2010; 107(19):8689-94. PMC: 2889301. DOI: 10.1073/pnas.1002720107. View

19.

Quenneville S, Verde G, Corsinotti A, Kapopoulou A, Jakobsson J, Offner S . In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol Cell. 2011; 44(3):361-72. PMC: 3210328. DOI: 10.1016/j.molcel.2011.08.032. View

20.

Ho L, Crabtree G . Chromatin remodelling during development. Nature. 2010; 463(7280):474-84. PMC: 3060774. DOI: 10.1038/nature08911. View