Distinct use of super-enhancer elements controls cell type–specific CD25 transcription and function
Rosanne Spolski, Peng Li, Vivek Chandra, Boyoung Shin, Shubham Goel, Keiko Sakamoto, Chengyu Liu, Jangsuk Oh, Min Ren, Yutaka Enomoto, Erin E. West, Stephen M. Christensen, Chi‐Keung Wan, Meili Ge, Jian-Xin Lin, Bingyu Yan, Majid Kazemian, Zu‐Xi Yu, Keisuke Nagao, Pandurangan Vijayanand, Ellen V. Rothenberg, Warren J. Leonard
Abstract
The IL-2 receptor α chain (IL-2Rα/CD25) is constitutively expressed on double-negative (DN2/DN3 thymocytes and regulatory T cells (T regs ) but induced by IL-2 on T and natural killer (NK) cells, with Il2ra expression regulated by a STAT5-dependent super-enhancer. We investigated CD25 regulation and function using a series of mice with deletions spanning STAT5-binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and T regs , with these mice developing autoimmune alopecia, whereas deleting an intronic region decreased IL-2–induced CD25 on peripheral T and NK cells. Thus, distinct super-enhancer elements preferentially control constitutive versus inducible expression in a cell type–specific manner. The mediator-1 coactivator colocalized with specific STAT5-binding sites. Moreover, both upstream and intronic regions had extensive chromatin interactions, and deletion of either region altered the super-enhancer structure in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating previously unknown ways to manipulate CD25 expression in a cell type–specific fashion.