NCoR1 Protects Mice From Dextran Sodium Sulfate–Induced Colitis by Guarding Colonic Crypt Cells From Luminal Insult

Abstract

Intestinal epithelial cell-specific nuclear receptor corepressor 1 (NCoR1)-deficient mice show increased susceptibility to chemical-induced ulcerative colitis. Colonic stem cell proliferation and secretory cell differentiation are regulated by NCoR1. Disruption of NCoR1 weakened barrier protection, allowing luminal products such as butyrate to penetrate and synergistically damage colonic crypt cells.BACKGROUND & AIMS: Colonic stem cells are essential for producing the mucosal lining, which in turn protects stem cells from insult by luminal factors. Discovery of genetic and biochemical events that control stem cell proliferation and differentiation can be leveraged to decipher the causal factors of ulcerative colitis and aid the development of more effective therapy. METHODS:We performed in vivo and in vitro studies from control (nuclear receptor corepressor 1 [NCoR1 F/F ]) and intestinal epithelial cell-specific NCoR1-deficient mice (NCoR1 DIEC ). Mice were challenged with dextran sodium sulfate to induce experimental ulcerative colitis, followed by colitis examination, barrier permeability analysis, cell proliferation immunostaining assays, and RNA sequencing analysis. By using crypt cultures, the organoid-forming efficiency, cell proliferation, apoptosis, and histone acetylation were analyzed after butyrate and/or tumor necrosis factor a treatments.RESULTS: NCoR1 DIEC mice showed a dramatic increase in disease severity in this colitis model, with suppression of proliferative cells at the crypt base as an early event and a concomitant increase in barrier permeability. Genome expression patterns showed an important role for NCoR1 in colonic stem cell proliferation and secretory cell differentiation. Colonic organoids cultured from NCoR1 DIEC mice were more sensitive to butyrate-induced cell growth inhibition and apoptosis, which were exaggerated further by tumor necrosis factor a cotreatment, which was accompanied by increased histone acetylation.CONCLUSIONS: NCoR1 regulates colonic stem cell proliferation and secretory cell differentiation. When NCoR1 is disrupted, barrier protection is weakened, allowing luminal products such as butyrate to penetrate and synergistically damage the colonic crypt cells. Transcript profiling: RNA sequencing data have been deposited in the GEO database, accession number: GSE136153.

Cldn-7 deficiency promotes experimental colitis and associated carcinogenesis by regulating intestinal epithelial integrity

“…Colonic stem cells are responsible for mucosal regeneration and the maintenance of stable colonic luminal environment, while the inner mucosa in turn protects colonic stem cells from damage by luminal contents. 41 Cldn-7 contributes to the maintenance of colonic epithelial integrity, whether there is a certain regulatory effect on colonic stem cells is unknown. In the next stage, we will explore the molecular mechanisms of how Cldn-7 and ISCs microenvironment influence the development and progression of CRC.…”

Interleukin-22 Ameliorates Dextran Sulfate Sodium-Induced Colitis through the Upregulation of lncRNA-UCL to Accelerate Claudin-1 Expression via Sequestering miR-568 in Mice

“…As we all known from the previous research, IEC apoptosis or cell death induced by DSS contributed to disruption of intestinal integrity [ 30 , 33 ]. The cleaved caspase-3 and PCNA results in IHC analysis showed that DSS induced the apoptosis and suppressed the proliferation of intestinal epithelial cells.…”

Regulation of Intestinal UDP-Glucuronosyltransferase 1A1 by the Farnesoid X Receptor Agonist Obeticholic Acid Is Controlled by Constitutive Androstane Receptor through Intestinal Maturation

“…IEC maturation stems from deep intestinal crypt cells proliferating and differentiating into the absorptive and secretory cell lineages that constitute the intestinal villi (Yeung et al, 2011;De Mey and Freund, 2013). The maturation process is tightly controlled through transcriptional repressive actions which include NCoR1, and if these repressive states are interrupted or released, accelerated proliferation and differentiation occurs (Mottis et al, 2013;Jo et al, 2015;Mennillo et al, 2020). We have currently established that the oral treatment of neonatal hUGT1 mice with isothiocyanates induces hepatic UGT1A1 through a CAR dependent mechanism that is directly linked to the development of hepatic oxidative stress (Yoda et al, 2017).…”