DNA methylation modulates transcription factor occupancy chiefly at sites of high intrinsic cell-type variability

The nuclear genome of every cell harbors millions of unoccupied transcription factor (TF) recognition sequences that harbor methylated cytosines. Although DNA methylation is commonly invoked as a repressive mechanism, the extent to which it actively silences specific TF occupancy sites is unknown. To define the role of DNA methylation in modulating TF binding, we quantified the effect of DNA methyltransferase abrogation on the occupancy patterns of a ubiquitous TF capable of autonomous binding to its target sites in chromatin (CTCF). Here we show that the vast majority of unoccupied, methylated CTCF recognition sequences remain unbound upon depletion of DNA methylation. Rather, methylation-regulated binding is restricted to a small fraction of elements that exhibit high intrinsic variability in CTCF occupancy across cell types. Our results suggest that DNA methylation is not a major groundskeeper of genomic transcription factor occupancy landscapes, but rather a specialized mechanism for stabilizing epigenetically labile sites.