The histone methyltransferase SETD2 modulates oxidative stress to attenuate experimental colitis

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. Setd2 Vil-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 Setd2 Vil-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.

Setd2 determines distinct properties of intestinal ILC3 subsets to regulate intestinal immunity

“…The generation of NKp46 + ILC3s is known to occur in 2-week-old mouse (Klose et al, 2013;Sawa et al, 2010), the process of which may be facilitated by the concomitant downregulation of Setd2 in ILC3s, considering a constraint function of Setd2 in NKp46 + ILC3 differentiation. Previous study has found that Setd2 expression is decreased in intestinal epithelial cells during experimental colitis (Liu et al, 2021). Another report has found that the adenosine 5 0 -monophosphate (AMP)-activated protein kinase (AMPK)-FOXO3 axis promotes SETD2 expression in a prostate cancer cell line (Baubec et al, 2015).…”

“…As the only characterized methyltransferase mediating histone H3 lysine 36 trimethylation (H3K36me3) in mammals, Setd2 has been shown to regulate the development and function of non-immune and immune cells through various mechanisms involving regulation of DNA methylation (Baubec et al, 2015;Morselli et al, 2015), histone modifications (Ferrari et al, 2014;Xu et al, 2019;Yuan et al, 2011), intragenic transcriptional initiation (Carrozza et al, 2005;Neri et al, 2017), alternative splicing (de Almeida et al, 2011), mRNA modification (Huang et al, 2019), and protein post-translational modification (Chen et al, 2017;Ji et al, 2019;Yuan et al, 2020). Mutation and changed expression of Setd2 have been reported in colitis and colon cancer, while the role of Setd2 in ILC3s has not been investigated (Liu et al, 2021;Yuan et al, 2017). Using Rorc Cre Setd2 f/f mice of both the wild-type and Rag1 À/À background, we have demonstrated that Setd2 fundamentally regulates the maintenance, subset commitment, and function of ILC3s.…”

SETD2 deficiency promotes renal fibrosis through the TGF-β/Smad signaling pathway in the absence of VHL

“…In addition, our recent studies reported that SETD2 plays important roles in intestinal immunity, suppressing intestinal inflammation, maternal epigenome, genomic imprinting and embryonic development, bone marrow mesenchymal stem cell differentiation, sperm development, and V(D)J recombination in normal lymphocyte development. [23][24][25][26][27][28][29][30][31] Moreover, SETD2 loss led to pancreatic carcinogenesis through preprint (which was not certified by peer review) is the author/funder. All rights reserved.…”

New Insights Into the Epigenetic Regulation of Inflammatory Bowel Disease

“…In addition, the epigenetic regulation disorder happened in the intestinal epithelial cells is also important in the pathogenesis and development of IBD. Liu et al found that SETD2, which is a trimethyltransferase of histone H3K36, can regulate oxidative stress to relieve inflammation in mice ( Liu et al, 2021 ). Specifically, increasing susceptibility to DSS-induced colitis would be came out after specific knockout Setd2 in villus cells.…”