Distinct use of super-enhancer elements controls cell type-specific CD25 transcription and function

The IL-2 receptor a chain (IL-2Ra/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. Overall design: ChIP-Seq analysis using various immune cells from wild-type and specific CRISPR-deletion mutants to investigate the Il2ra super-enhancer and mechanisms by which cell-type specific or developmental specific expression of this gene is controlled. HiChIP experiments using CD8+ T cells were performed to reveal H3K27Ac-mediated chromatin interactions among the Il2ra promoter in wile-type and mutants.