Colorectal cancer (CRC) ranks among the leading causes of cancer-related deaths in the world. The cancer genome is characterized by changes in chromatin modification patterns and a driving therapeutic goal is to re-pattern the epigenome to resemble a normal cell of that same tissue. However, it is necessary to first define the exact epigenomic patterns that contribute to the disease. We are taking several approaches, such as 1) identifying enhancers that show changes in methylation in CRC using large numbers of tumors from The Cancer Genome Atlas, 2) comparing ChIP-seq patterns of modified histones in normal vs. tumor colon cells, and 3) using GWAS combined with epigenomic information to identify enhancers that harbor SNPs that are associated with an increased risk of CRC. We then employ genomic nucleases (TALENs and CRISPRs) to precisely delete these CRC-associated enhancers from the human genome. When coupled with RNA-seq and 3C analyses, this will identify the genes regulated directly and indirectly by each enhancer. As a next step, we wish to design an effective treatment to alter the epigenetic profile at these CRC-associated enhancers. Several drugs have been developed to target the epigenome. However, these drugs alter the expression of thousands of genes and have many off-target effects. A more rationale approach may be to epigenetically modify specific loci, rather than affecting the entire epigenome. We are developing site-specific epigenetic toggle switches (DNA targeting platforms fused to epigenetic modifying domains) and will examine their ability to specifically affect transcription of CRC-associated genes.