Abstract: The maintenance of gene repression is crucial for the prevention of cancer development and progression. PRC2 (Polycomb repressive complex 2) regulates the transcriptional repression of oncogenes through the tri-methylation of histone H3 at lysine 27 (H3K27me3), which is accomplished by the PRC2 catalytic subunit EZH2. Aberrant expression of EZH2 can lead to the onset of several highly aggressive cancers including prostate, breast, lung, melanoma, lymphoma, and pancreatic cancer. Efficient methyltransferase activity of EZH2 in vivo is dependent on the presence of the PHD finger protein 1 (PHF1), however the mechanism by which PHF1 regulates EZH2 is poorly understood. We hypothesize that PHF1 interacts directly with EZH2 at gene promoters and stimulates tri-methylation of H3K27, thereby facilitating silencing at key genes. Here we report our findings from binding studies of the EZH2-PHF1 complex and the effects of PHF1 on EZH2 methyltransferase activity.