Transcription factors as readers and effectors of DNA methylation

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. Evidence is emerging that transcription factors (TFs) lacking methyl-CpG binding domains can interact with methylated DNA. This Analysis article reviews the in vitro and in vivo evidence for methylation-mediated interactions between TFs and DNA, and their functional consequences. 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