1. Cutting Edge: Hypoxia-Induced Ubc9 Promoter Hypermethylation Regulates IL-17 Expression in Ulcerative Colitis.
- Author
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Kumar R, Singh AK, Starokadomskyy P, Luo W, Theiss AL, Burstein E, and Venuprasad K
- Subjects
- Animals, Colitis, Ulcerative pathology, Colon pathology, Humans, Hypoxia pathology, Inflammation genetics, Inflammation pathology, Intestinal Mucosa pathology, Mice, Mice, Inbred C57BL, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Th17 Cells, Colitis, Ulcerative genetics, DNA Methylation genetics, Hypoxia genetics, Interleukin-17 genetics, Promoter Regions, Genetic genetics, Ubiquitin-Conjugating Enzymes genetics
- Abstract
Dysregulated IL-17 expression is central to the pathogenesis of several inflammatory disorders, including ulcerative colitis. We have shown earlier that SUMOylation of ROR-γt, the transcription factor for IL-17, regulates colonic inflammation. In this study, we show that the expression of Ubc9, the E2 enzyme that targets ROR-γt for SUMOylation, is significantly reduced in the colonic mucosa of ulcerative colitis patients. Mechanistically, we demonstrate that hypoxia-inducible factor 1α (HIF-1α) binds to a CpG island within the Ubc9 gene promoter, resulting in its hypermethylation and reduced Ubc9 expression. CRISPR-Cas9-mediated inhibition of HIF-1α normalized Ubc9 and attenuated IL-17 expression in Th17 cells and reduced diseases severity in Rag1
-/- mice upon adoptive transfer. Collectively, our study reveals a novel epigenetic mechanism of regulation of ROR-γt that could be exploited in inflammatory diseases., (Copyright © 2021 by The American Association of Immunologists, Inc.)- Published
- 2021
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