DNA methylation patterns are established and maintained by three DNA 
methyltransferases (DNMT): DNMT1, DNMT3A, and DNMT3B. Although essential for 
development, methylation patterns are frequently disrupted in cancer and 
contribute directly to carcinogenesis. Recent studies linking polycomb group 
repression complexes (PRC1 and PRC2) to the DNMTs have begun to shed light on 
how methylation is targeted. We identified previously a panel of genes regulated 
by DNMT3B. Here, we compare these with known polycomb group targets to show that 
approximately 47% of DNMT3B regulated genes are also bound by PRC1 or PRC2. We 
chose 44 genes coregulated by DNMT3B and PRC1/PRC2 to test whether these 
criteria would accurately identify novel targets of epigenetic silencing in 
colon cancer. Using reverse transcription-PCR, bisulfite genomic sequencing, and 
pyrosequencing, we show that the majority of these genes are frequently silenced 
in colorectal cancer cell lines and primary tumors. Some of these, including 
HAND1, HMX2, and SIX3, repressed cell growth. Finally, we analyzed the histone 
code, DNMT1, DNMT3B, and PRC2 binding by chromatin immunoprecipitation at 
epigenetically silenced genes to reveal a novel link between DNMT3B and the mark 
mediated by PRC1. Taken together, these studies suggest that patterns of 
epigenetic modifiers and the histone code influence the propensity of a gene to 
become hypermethylated in cancer and that DNMT3B plays an important role in 
regulating PRC1 function.