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- Title
Distinct use of super-enhancer elements controls cell type–specific CD25 transcription and function.
- Authors
Spolski, Rosanne; Li, Peng; Chandra, Vivek; Shin, Boyoung; Goel, Shubham; Sakamoto, Keiko; Liu, Chengyu; Oh, Jangsuk; Ren, Min; Enomoto, Yutaka; West, Erin E.; Christensen, Stephen M.; Wan, Edwin C. K.; Ge, Meili; Lin, Jian-Xin; Yan, Bingyu; Kazemian, Majid; Yu, Zu-Xi; Nagao, Keisuke; Vijayanand, Pandurangan
- Abstract
The IL-2 receptor α chain (IL-2Rα/CD25) is constitutively expressed on double-negative (DN2/DN3 thymocytes and regulatory T cells (Tregs) 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 Tregs, 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. Editor's summary: Regulation of the gene encoding IL-2Rα (CD25) has been studied extensively to understand discrete patterns of expression on lymphocyte subsets, including the influence of Il2ra super-enhancer elements. Spolski et al. undertook an exhaustive investigation of CD25 regulation and function using a panel of mice bearing different deletions within Il2ra super-enhancer elements that modulate binding of STAT5. Deletion of the upstream super-enhancer region markedly affected constitutive CD25 expression on double-negative (DN)2/DN3 thymocytes and Tregs and resulted in the development of mice with autoimmune alopecia. By contrast, deletion of an intronic region reduced IL-2–driven CD25 expression on peripheral NK and T cells. The upstream and intronic regions also exhibited chromatin interactions, and deletions resulted in changes in super-enhancer structures in mature T cells. These findings highlight roles of different super-enhancer elements in controlling CD25 expression. —Christiana Fogg
- Subjects
CD25 antigen; T cell receptors; REGULATORY T cells; LYMPHOCYTE subsets; GENE expression; KILLER cells
- Publication
Science Immunology, 2023, Vol 8, Issue 89, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adi8217