Cutting edge: Hypoxia-induced ubc9 promoter hypermethylation regulates il-17 expression in ulcerative colitis

Ritesh Kumar, Amir Kumar Singh, Petro Starokadomskyy, Weibo Luo, Arianne L. Theiss, Ezra Burstein, Venuprasad Poojary

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)936-940
Number of pages5
JournalJournal of Immunology
Volume206
Issue number5
DOIs
StatePublished - Mar 1 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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