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

Abstract

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 [NCoR1F/F]) and intestinal epithelial cell-specific NCoR1-deficient mice (NCoR1ΔIEC). 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 α treatments.

RESULTS:

NCoR1ΔIEC 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 NCoR1ΔIEC mice were more sensitive to butyrate-induced cell growth inhibition and apoptosis, which were exaggerated further by tumor necrosis factor α co-treatment, 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.

• Authors: Elvira Mennillo, Xiaojing Yang, Miles Paszek, Johan Auwerx, Christopher Benner, Shujuan Chen
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 10 Issue 1 Pg. 133-147 ( 2020) ISSN: 2352-345X [Electronic] United States
• PMID: 32044398 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Butyrates
• Histones
• Ncor1 protein, mouse
• Nuclear Receptor Co-Repressor 1
• Dextran Sulfate

Topics

• Acetylation
• Adult Stem Cells (drug effects, pathology)
• Animals
• Apoptosis (drug effects, genetics)
• Butyrates (pharmacology)
• Cell Proliferation (drug effects, genetics)
• Colitis, Ulcerative (chemically induced, genetics, pathology)
• Colon (cytology, pathology)
• Dextran Sulfate (administration & dosage, toxicity)
• Disease Models, Animal
• Epigenesis, Genetic
• Epithelial Cells (pathology)
• Female
• Histones
• Humans
• Intestinal Mucosa (cytology, drug effects, pathology)
• Male
• Mice
• Mice, Transgenic
• Nuclear Receptor Co-Repressor 1 (genetics, metabolism)
• Organoids
• Primary Cell Culture