Title | The histone methyltransferase SETD2 modulates oxidative stress to attenuate experimental colitis |
Authors | Liu, Min Rao, Hanyu Liu, Jing Li, Xiaoxue Feng, Wenxin Gui, Liming Tang, Huayuan Xu, Jin Gao, Wei-Qiang Li, Li |
Affiliation | Shanghai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Renji Med X Clin Stem Cell Res Ctr, Ren Ji Hosp,Sch Med, Shanghai 200127, Peoples R China Shanghai Jiao Tong Univ, Sch Biomed Engn, Shanghai 200127, Peoples R China Shanghai Jiao Tong Univ, Med X Res Inst, 160 Pujian Rd, Shanghai 200127, Peoples R China Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, State Key Lab Chem Oncogen, Shenzhen, Peoples R China |
Keywords | INFLAMMATORY-BOWEL-DISEASE ULCERATIVE-COLITIS EPITHELIAL BARRIER MOUSE MODELS METHYLATION MICROBIOTA CHROMATIN MICE HOMEOSTASIS MUTATIONS |
Issue Date | Jul-2021 |
Publisher | REDOX BIOLOGY |
Abstract | 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. |
URI | http://hdl.handle.net/20.500.11897/614571 |
ISSN | 2213-2317 |
DOI | 10.1016/j.redox.2021.102004 |
Indexed | SCI(E) |
Appears in Collections: | 深圳研究生院待认领 |