DNA methylation shapes transcription factor binding beyond canonical CpG contexts - array 6

Our results reveal extensive TF sensitivity to methylation state, position, and strand orientation—including strong binding of several TFs to non-CpG and hemi-methylated sites.

The presence of 5mC can dramatically alter TF-DNA interactions: transforming low-affinity sites into high-affinity ones by enabling new contacts, or silencing otherwise favorable motifs through steric hindrance. Genomic analyses further show that the methylation-sensitive sequences identified in vitro are represented within enhancers and regulatory elements, exhibiting distinct methylation patterns across cell types. Together, our findings uncover a previously hidden layer of methylation-dependent TF-DNA recognition, broadening the understanding of epigenetics in transcriptional regulation.