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Transcription factors as readers and effectors of DNA methylation

Nature Reviews Genetics volume 17, pages 551–565 (2016)Cite this article

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Key Points

  • Epigenetic profiling has been extensively undertaken in different systems, including development and disease. However, functional characterization of the dynamics of epigenomes, which will provide mechanistic insights into the role of epigenetics in diverse biological systems, remains largely unexplored.

  • Proteins with a methyl-CpG binding domain (MBD) are well-studied readers and effectors of DNA methylation. Transcription factors (TFs) are now emerging as a new class of DNA methylation readers and effectors that translate DNA methylation signals into biological actions.

  • Different high-throughput approaches, including tandem mass spectrometry (MS/MS), protein microarray, DNA microarray and chromatin immunoprecipitation followed by bisulfite sequencing (ChIP–BS-seq), have identified almost 100 TFs that interact with methylated DNA in vitro. A few of these have been confirmed to bind methylated DNA in vivo.

  • Two models may explain the relationship between TF binding and DNA methylation. Although some TFs can affect the DNA methylation status at the genomic regions near their binding sites, the interaction of other TFs with DNA is dependent on DNA methylation within their respective binding sites.

  • The interactions between TFs and methylated DNA could impact various processes, including gene expression regulation, splicing regulation, chromatin remodelling and disease.

  • Besides conventional CpG methylation, non-CpG methylation and other methylation derivatives (including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC)), have also been profiled in different cell types. Many proteins found to interact with these modifications were determined to be TFs.

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.

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Figure 1: Interaction modes between proteins and DNA.
Figure 2: Methylated-DNA–TF interactions in vivo.
Figure 3: Two action models between TF and methylated DNA interactions.
Figure 4: Possible biological consequences of methylated DNA–TF interactions.

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Acknowledgements

The authors thank J. Wan, Y. Zhao and other laboratory members from the Zhu and Qian groups for their discussions. The authors are supported in part by the NIH (EY024580, EY023188 to J.Q. and GM111514 to H.Z.).

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Authors and Affiliations

  1. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Edward Miller Research Building, 733 North Broadway, Baltimore, 21205, Maryland, USA

    Heng Zhu

  2. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, 21287, Maryland, USA

    Heng Zhu & Jiang Qian

  3. The Wilmer Eye Institute, Johns Hopkins School of Medicine, The Smith Building, 400 North Broadway, Baltimore, 21287, Maryland, USA

    Guohua Wang & Jiang Qian

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  1. Heng Zhu
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Supplementary information

Supplementary information S1 (figure)

Methylation levels at TAF1 binding peaks. (PDF 171 kb)

Glossary

DNA methylation

A biological process in which a methyl group is covalently added to a cytosine.

DNA methyltransferases

(DNMTs). Enzymes that catalyse the transfer of a methyl group to DNA.

CpG islands

A segment of DNA with a high frequency of CpG dinucleotides that often overlaps with promoters.

Genomic imprinting

A phenomenon by which some genes are expressed in an allele-specific manner; that is, alleles inherited either from the father or the mother are expressed.

Deep sequencing

A next-generation sequencing approach (for example, RNA sequencing or bisulfite sequencing) with high coverage.

Methylome

The collection of methylation status in an entire genome.

Epigenome

The collection of chemical modifications added to DNA or histones of a given genome, which do not alter the genetic codes but can be inherited and lead to changes in the function of the genome.

Differentially methylated regions

Regions of DNA with significant differences in methylation levels between two physiological conditions (for example, disease versus healthy) different developmental stages or different tissues.

K d

The dissociation constant Kd is defined by the Koff/Kon ratio, which has the unit of concentration.

Oblique incidence reflectivity difference

(OIRD). A form of polarization-modulated imaging ellipsometer for label-free, high-throughput detection of binding events on protein microarrays.

Kon and Koff

In a simple binding event, Kon and Koff refer to the on-rate and off-rate constants, which have units of 1/(concentration time) and 1/time, respectively.

TETs

(Ten-eleven translocation proteins). The TET family of methylcytosine dioxygenases is made of TET1, TET2, TET3 and TET4, which catalyse the conversion of the modified DNA base 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC).

Topologically associated domains

3D spatial organization units of mammalian genomes, within which most enhancer–promoter interactions occur.

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Zhu, H., Wang, G. & Qian, J. Transcription factors as readers and effectors of DNA methylation. Nat Rev Genet 17, 551–565 (2016). https://doi.org/10.1038/nrg.2016.83

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