Title: The Conserved Non-coding Sequences CNS6 and CNS9 Control Cytokine-Induced Rorc Transcription during T Helper 17 Cell Differentiation
Author: Dehui Chang, Qi Xing, Yang Su, Xiaohong Zhao, Wei Xu, Xiaohu Wang, Chen Dong
Abstract: RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells whoseupregulation in developing Th17 cells is critically regulated by interleukin-6 (IL-6)and TGF-β, the molecular mechanisms of which remain largely unknown. Here we identifiedconserved non-coding sequences (CNSs) 6 and 9 at the Rorc gene, essential for its expression during Th17 cell differentiation but not requiredfor RORγt expression in innate lymphocytes and γδ T cells. Mechanistically, the IL-6-signaltransducer and activator of transcription 3 (STAT3) axis appeared to be largely dependenton CNS9 and only partially on CNS6 in controlling RORγt expression and epigeneticactivation of the Rorc locus. TGF-β alone was sufficient to induce RORγt expression in a CNS6- but not CNS9-dependentmanner through CNS6 binding by SMAD proteins. Our study reveals an important synergisticmechanism downstream of IL-6 and TGF-β in regulation of RORγt expression and Th17cell commitment via distinct cis-regulatory elements.