SRA

The majority of CpG dinucleotides in the human genome are methylated at cytosine bases. The methylation is heritable across cell divisions, and contributes to the epigenetic memory that maintains the differentiated state of distinct cell types. Active gene regulatory elements are generally undermethylated relative to their flanking regions, and the undermethylation is thought to be important for their activity. Consistently with this model, the binding of many transcription factors (TFs) is diminished by methylation of their target sequences. However, the effect of cytosine methylation on TF binding has not been systematically characterized. Here we show that CpG methylation has a major impact on TF binding, and that different structural classes of TFs display different preferences for mCpG. Of the 534 TFs that we analyzed, ~ 40% were affected by CpG methylation. Binding of most major classes of TFs, including bHLH, bZIP, and ETS was inhibited by mCpG; such TFs were commonly involved in cell maintenance processes. In contrast, TFs that preferred to bind to methylated DNA mainly represented homeodomain, POU and NFAT proteins, and were enriched in TFs with central roles in stem cell regulation, developmental processes and differentiation. Our results provide the first systematic examination of the effect of an epigenetic DNA modification on TF binding, and suggest that the role of CpG methylation on gene regulation is more context-specific than what has previously been appreciated.