Mismatch Repair-Signature Mutations Activate Gene Enhancers Across Human Colorectal Cancer Epigenomes

Elife. 2019 Feb 13;8:e40760. doi: 10.7554/eLife.40760.

Abstract

Commonly-mutated genes have been found for many cancers, but less is known about mutations in cis-regulatory elements. We leverage gains in tumor-specific enhancer activity, coupled with allele-biased mutation detection from H3K27ac ChIP-seq data, to pinpoint potential enhancer-activating mutations in colorectal cancer (CRC). Analysis of a genetically-diverse cohort of CRC specimens revealed that microsatellite instable (MSI) samples have a high indel rate within active enhancers. Enhancers with indels show evidence of positive selection, increased target gene expression, and a subset is highly recurrent. The indels affect short homopolymer tracts of A/T and increase affinity for FOX transcription factors. We further demonstrate that signature mismatch-repair (MMR) mutations activate enhancers using a xenograft tumor metastasis model, where mutations are induced naturally via CRISPR/Cas9 inactivation of MLH1 prior to tumor cell injection. Our results suggest that MMR signature mutations activate enhancers in CRC tumor epigenomes to provide a selective advantage.

Keywords: cancer biology; cis-regulatory mutation; colorectal cancer; gene enhancer; genetics; genomics; human.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • DNA Mismatch Repair / genetics*
  • Enhancer Elements, Genetic / genetics*
  • Epigenome*
  • Gene Expression Regulation
  • Histones / metabolism
  • Humans
  • INDEL Mutation / genetics
  • Lysine / metabolism
  • Mice
  • Microsatellite Instability
  • Mutation / genetics*
  • Nucleotide Motifs / genetics
  • Phenotype
  • Selection, Genetic
  • Transcription Factors / metabolism

Substances

  • Histones
  • Transcription Factors
  • Lysine