The correlation between DNA methylation and a subset of histone 
post-translational modifications (positive and negative) has hinted at an 
underlying regulatory crosstalk between histone marks and DNA methylation in 
patterning the human DNA methylome, an idea further supported by corresponding 
alterations to both histone marks and DNA methylation during malignant 
transformation. This study investigated the framework by which histone marks 
influence DNA methylation at a genome-wide level. Using RNAi in a pluripotent 
human embryonic carcinoma cell line we depleted essential components of the 
MLL/COMPASS, polycomb repressive complex 2 (PRC2), and PRC1 histone modifying 
complexes that establish, respectively, the post-translational modifications 
H3K4me3, H3K27me3, and H2AK119ub, and assayed the impact of the subsequent 
depletion of these marks on the DNA methylome. Absence of H2AK119ub resulted 
predominantly in hypomethylation across the genome. Depletion of H3K4me3 and, 
surprisingly, H3K27me3 caused CpG island hypermethylation at a subset of loci. 
Intriguingly, many promoters were co-regulated by all three histone marks, 
becoming hypermethylated with loss of H3K4me3 or H3K27me3 and hypomethylated 
with depletion of H2AK119ub, and many of these co-regulated loci were among 
those commonly targeted for aberrant hypermethylation in cancer. Taken together, 
our results elucidate novel roles for polycomb and MLL/COMPASS in regulating DNA 
methylation and define targets of this regulation.