Abstract
CpG methylation promotes binding of a subset of transcription factors and inhibits binding of others.
Major finding: CpG methylation promotes binding of a subset of transcription factors and inhibits binding of others.
Approach: Binding preferences of 542 transcription factors to methylated or unmethylated DNA were analyzed by SELEX.
Impact: CpG methylation may selectively alter transcription factor binding to influence transcriptional regulation.
In the human genome the majority of CpG dinucleotides are methylated. However, there is variation in the methylation patterns with highly expressed genes exhibiting hypermethylation in the gene body and hypomethylation at regulatory elements, and different cell types displaying dissimilar methylation patterns. Further, CpG methylation has been shown to prevent binding of some transcription factors, but the effect of cytosine methylation on transcription factor binding has not been determined globally. Yin and colleagues performed high-throughput systematic evolution of ligands by exponential enrichment (HT-SELEX) analysis using methylated and unmethylated DNA to determine the effect cytosine methylation on the DNA binding of 542 human transcription factors. This method identified binding motifs for a number of transcription factors that had not been previously characterized. CpG methylation had little effect on the binding of 39% of transcription factors, including those that bound to CpG-free regions. In contrast, 23% of transcription factors bound more weakly (or not at all) to methylated CpGs, and 34% of transcription factors preferentially bound methylated CpGs. These findings suggest that CpG methylation can both enhance and suppress transcription factor binding. Binding of transcription factors in the bHLH, bZIP, and ETS families was generally inhibited by CpG methylation due to increased steric hindrance, whereas homeodomain, POU, and NFAT transcription factors bound preferentially to methylated CpGs due to direct hydrophobic interactions with the 5-methyl group of methylcytosine. Moreover, transcription factors essential for development often preferentially bound to methylated CpGs. Altogether, these results indicate that CpG methylation can both positively and negatively affect transcription factor binding, and thus may influence cell differentiation and transcriptional regulation. Further, these findings may be relevant in cancer where epigenetic dysregulation may lead to altered transcription factor binding.
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