Abstract 4531: Dynamic long-range chromatin interaction controls expression of Il-21 in CD4+ T cells

Abstract

Abstract IL-21, a member of four-α-helical bundle type I cytokines, causes many pleiotropic effects, including terminal differentiation of B cells, immunoglobulin production, and the development of follicular helper T cells. IL-21 also promotes differentiation of Th17 cells and is implicated in the development of autoimmune disease. IL-21 can be strongly induced in CD4+ T cells by IL-6; however, very little is known about the mechanisms underlying the transcriptional regulation of the Il-21 gene at the chromatin level. Here, we identified insulator elements in the Il-21 locus with enhancer-blocking activity, which constitutively bind CTCF and cohesin. In naïve CD4+ T cells, these upstream and downstream CTCF-binding sites interact with each other to make a DNA loop; however, the Il-21 promoter does not interact with any cis-elements in the Il-21 locus. In contrast, stimulation of CD4+ T cells with IL-6 in the presence of αCD3 and αCD28 leads to recruitment of STAT3 and NFAT transcription factors to the promoter, as well as to novel distal enhancer region. This induces dynamic changes in chromatin configuration, bringing the promoter and the regulatory elements in close spatial proximity, facilitating IL-21 expression. The long-range interaction between the promoter and distal enhancer region was dependent on JAK/STAT3 signaling pathway but was disrupted in regulatory T cells, where IL-21 expression was repressed. In addition, we demonstrated that CTCF was required for optimal IL-21 expression and formation of chromatin looping in the Il-21 locus. Thus, our work uncovers a novel topological chromatin framework underlying proper transcriptional regulation of Il-21 gene. Citation Format: Yeeun Choi. Dynamic long-range chromatin interaction controls expression of Il-21 in CD4+ T cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4531.