Cutting Edge: Hypoxia-Induced Ubc9 Promoter Hypermethylation Regulates IL-17 Expression in Ulcerative Colitis

Dysregulated IL-17 expression is central to the pathogenesis of several inflammatory disorders, including ulcerative colitis. We have shown earlier that SUMOylation of ROR-gamma t, 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-gamma t for SUMOylation, is significantly reduced in the colonic mucosa of ulcerative colitis patients. Mechanistically, we demonstrate that hypoxia-inducible factor 1 alpha (HIF-1 alpha) binds to a CpG island within the Ubc9 gene promoter, resulting in its hypermethylation and reduced Ubc9 expression. CRISPR-Cas9-mediated inhibition of HIF-1 alpha 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-gamma t that could be exploited in inflammatory diseases.

Automated summary

This study reveals that the expression of Ubc9 is significantly reduced in the colonic mucosa of ulcerative colitis patients, due to hypermethylation by hypoxia-inducible factor 1 alpha (HIF-1 alpha). Inhibiting HIF-1 alpha with CRISPR-Cas9 technology can normalize Ubc9 expression and attenuate IL-17 expression in Th17 cells.