Genetic mutations or regulatory failure underlies cellular malfunction in many diseases including colorectal cancer (CRC) and Inflammatory bowel diseases (IBD). However, mutational defects alone fail to explain the complexity of such disorders. Epigenetic regulation – control of gene action through chemical and structural changes of chromatin – provides a platform to integrate multiple extracellular inputs and prepares the cellular genome for appropriate gene expression responses. Coregulation by Polycomb Repressive Complex 2 (PRC2) mediated trimethylation of Lysine 27 on Histone 3 (H3K27me3) and DNA methylation has emerged as one of the most influential epigenetic control in CRC and many other diseases, but molecular details remain inadequate.