Mismatch-repair signature mutations activate gene enhancers across human colorectal cancer epigenomes

We show that mismatch-repair (MMR) signature mutations can activate colorectal cancer (CRC)-specific enhancers, through analysis of enhancer DNA associated with the active enhancer histone mark H3K27ac. We demonstrate that MMR mutations activate enhancers using a xenograft metastasis model, where mutations are induced naturally via CRISPR/Cas9 inactivation of MLH1 prior to tumor cell injection. H3K27ac profiles of LoVo cells, 2 parental WT COLO-205 subclones, 2 MLH1-/- COLO-205 subclones, and 7 xenograft tumors derived from the COLO-205 subclones.