KDM2A and KDM2B cooperatively protect a subset of CpG Islands from DNA methylation [ChIP-seq]

In the mammalian genome, most CpGs are methylated, however, regions of the genome known as CpG islands (CGIs) are largely unmethylated, which are closely associated with modulating gene expression. The KDM2 proteins (KDM2A and KDM2B) are recruited via their ZF-CxxC domains to CGIs and mediate demethylation of H3K36me2 at these regions. However, the mechanism whether and how KDM2 proteins protect CGIs from DNA methylation remains unknown. Here, we report that depletion of each or both KDM2 proteins, or mutation JmjC domains of KDM2 proteins, leads to a modest increase of DNA methylation at CGIs, but a significant increase at CGI shores. Depletion of both KDM2 proteins shows most obvious increase of DNA methylation, indicating that KDM2A and KDM2B cooperatively regulate DNA methylation at CGIs. We further show that DNA methylation in the absence of KDM2 proteins show more obvious increase at a subset of CpG Islands such as non-marked and H3K27me3-only CGIs than other CpG Islands like bivalent and H3K4me3-only CGIs. Taken together, our finding reveals the role for KDM2 proteins in regulating DNA methylation at CGIs, and uncovers the mechanism by which complex chromatin state including histone modifications and CGI binding proteins synergistically protect CGIs from DNA methylation.