De novoDNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands

AbstractThe aberrant gain of DNA methylation at CpG islands (CGIs) is frequently observed in colorectal tumours and may silence the expression of tumour suppressors such asMLH1. Current models propose that these CGIs are targeted byde novoDNA methyltransferases (DNMTs) in a sequence-specific manner but this has not been tested. Using ectopically integrated CGIs, we find that aberrantly methylated CGIs are subject to low levels ofde novoDNMT activity in colorectal cancer cells. By delineating DNMT targets, we find that insteadde novoDNMT activity is targeted primarily to CGIs marked by the histone modification H3K36me3, a mark associated with transcriptional elongation. These H3K36me3 marked CGIs are heavily methylated in colorectal tumours and the normal colon suggesting thatde novoDNMT activity at CGIs in colorectal cancer is focused on similar targets to normal tissues and not greatly remodelled by tumourigenesis.