Role of DNA Methylation in Modulating Transcription Factor Occupancy

•Most CTCF binding in vivo is unaltered by genomic abrogation of DNA methylation•A limited set of CTCF sites from other cell lineages is methylation sensitive•Methylation-sensitive CTCF sites are highly variable across cell types•Key sequence and chromatin features predict methylation sensitivity of CTCF binding

SummaryAlthough DNA methylation is commonly invoked as a mechanism for transcriptional repression, the extent to which it actively silences transcription factor (TF) occupancy sites in vivo is unknown. To study the role of DNA methylation in the active modulation of TF binding, we quantified the effect of DNA methylation depletion on the genomic occupancy patterns of CTCF, an abundant TF with known methylation sensitivity that is capable of autonomous binding to its target sites in chromatin. Here, we show that the vast majority (>98.5%) of the tens of thousands of unoccupied, methylated CTCF recognition sequences remain unbound upon abrogation of DNA methylation. The small fraction of sites that show methylation-dependent binding in vivo are in turn characterized by highly variable CTCF occupancy across cell types. Our results suggest that DNA methylation is not a primary groundskeeper of genomic TF landscapes, but rather a specialized mechanism for stabilizing intrinsically labile sites.

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