TY - JOUR
T1 - Cutting edge
T2 - Hypoxia-induced ubc9 promoter hypermethylation regulates il-17 expression in ulcerative colitis
AU - Kumar, Ritesh
AU - Singh, Amir Kumar
AU - Starokadomskyy, Petro
AU - Luo, Weibo
AU - Theiss, Arianne L.
AU - Burstein, Ezra
AU - Venuprasad, K.
N1 - Publisher Copyright:
© 2021 by The American Association of Immunologists, Inc.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.2000015
DO - 10.4049/jimmunol.2000015
M3 - Article
C2 - 33504619
AN - SCOPUS:85101238505
SN - 0022-1767
VL - 206
SP - 936
EP - 940
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -