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Loss of colonic epithelial NCOR1 aggravates experimental colitis chronicity
Author(s) -
Boudreau Francois,
Lecours Mia,
Di Castro Ariane Cristina,
Nicolas Vilcy Reyes,
Jones Christine,
Perreault Nathalie
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04579
Subject(s) - inflammation , biology , cancer research , colitis , repressor , downregulation and upregulation , gene , microbiology and biotechnology , gene expression , immunology , genetics
The nuclear co‐repressor NCOR1 orchestrates the assembly of a large transcriptional repression complex that is involved in the negative regulation of pro‐inflammatory genes. Chronic intestinal inflammation is associated with sustained activation of pro‐inflammatory molecules. Since NCOR1 is considered as a potent repressor of pro‐inflammatory genes in macrophages, we aimed to investigate the role of intestinal epithelial NCOR1 during inflammatory stresses. Conditional deletion of Ncor1 in the whole intestinal epithelium was achieved by crossing Villin‐Cre and Ncor1 loxP/loxP C57BL/6 mouse models. DSS‐induced colitis in NCOR1 Δ IEC mice was more severe than control mice according to survival as well as clinical observations. A gene profiling analysis in the colon of non‐diseased NCOR1 Δ IEC and control mice identified 85 unique and mapped transcripts being significantly modulated between NCOR1 Δ IEC and control mice. An Ingenuity Pathway Analysis from these predicted target genes identified gastrointestinal disease (79 transcripts) as top disease and biofunction. Analysis of enriched targets in specific canonical pathways predicted an increase in the tryptophan degradation pathway ( P = 3.2E‐02), a pathway recently demonstrated to be strongly relevant to inflammatory bowel disease severity. Indoleamine‐pyrrole 2,3‐dioxygenase (IDO1), that catalyzes the first and rate‐limiting step of tryptophan oxidation, was induced more than 7 times in the colon of NCOR1 Δ IEC mice. IDO1 was also significantly more elevated in NCOR1 Δ IEC mice when compared to control mice both subjected to chronic inflammation (3 cycles of DSS). Spontaneous induction of Ido1 gene expression was also confirmed in cultured ex vivo colon organoids deleted for Ncor1 . In conclusion, our results highlight the critical role of NCOR1 to maintain intestinal inflammatory homeostasis during experimental colitis and uncover a novel function for NCOR1 in the regulation of Ido1 expression and potentially tryptophan metabolism. Support or Funding Information Canadian Institutes of Health Research