The histone methyltransferase SETD2 modulates oxidative stress to attenuate experimental colitis

Redox Biol. 2021 Jul;43:102004. doi: 10.1016/j.redox.2021.102004. Epub 2021 May 13.


Epigenetic regulation disorder is important in the onset and pathogenesis of inflammatory bowel disease (IBD). SETD2, a trimethyltransferase of histone H3K36, is frequently mutated in IBD samples with a high risk of developing colorectal cancer (CRC). However, functions of SETD2 in IBD and colitis-associated CRC remain largely undefined. Here, we found that SETD2 modulates oxidative stress to attenuate colonic inflammation and tumorigenesis in mice. SETD2 expression became decreased in IBD patients and dextran sodium sulfate (DSS)-induced colitic mice. Setd2Vil-KO mice showed increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption and markedly increased intestinal permeability that subsequently facilitated inflammation-associated CRC. Mechanistically, we found that Setd2 depletion resulted in excess reactive oxygen species (ROS) by directly down-regulating antioxidant genes, which led to defects in barrier integrity and subsequently inflammatory damage. Moreover, overexpression of antioxidant PRDX6 in Setd2Vil-KO intestinal epithelial cells (IECs) largely alleviated the overproductions of ROS and improved the cellular survival. Together, our findings highlight an epigenetic mechanism by which SETD2 modulates oxidative stress to regulate intestinal epithelial homeostasis and attenuate colonic inflammation and tumorigenesis. SETD2 might therefore be a pivotal regulator that maintains the homeostasis of the intestinal mucosal barrier.

Keywords: Epithelial barrier; IBD; Oxidative stress; ROS; SETD2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis* / genetics
  • Colon / metabolism
  • Dextran Sulfate
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Histone Methyltransferases / metabolism
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress


  • Dextran Sulfate
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • SETD2 protein, human
  • SETD2 protein, mouse