Control of IL-2Rα gene expression: Structural changes within the proximal enhancer/core promoter during T-cell development

Abstract

During T-cell development in thymus, CD25, the IL-2 receptor α chain (IL-2Rα) is already expressed in early double-negative (DN) thymocytes where commitment to T-cell lineage has been established, but subsequently IL-2Rα is dramatically down-regulated for the remainder of T-cell development. The loss of IL-2Rα expression after expression of the pre-TCR α:β complex on the cell surface is essential for the later specific responses of mature T cells. Using appropriate mouse models and DMS genomic footprinting, we showed that the TATA box in the core promoter region of the murine IL-2Rα locus was occupied only in DN CD25+ T cells. Further, by chromatin immunoprecipitation assays, we evidenced that down-regulation of IL-2Rα transcription correlated with (i) loss of the basal transcriptional machinery; (ii) dissociation of histone acetylase p300 and BRG1, a member of the ATP-dependent chromatin remodeling complex SWI/SNF; and (iii) histone N-termini dephosphorylation plus deacetylation. In contrast, occupancy of the proximal enhancer region (positive regulatory region I) was not detected by in vivo genomic footprinting though constitutive accessibility of the promoter region for DNase I digestion both in the DN and double-positive stages correlated with the constitutive association of CBP and PCAF to the IL-2Rα core promoter. These results exemplify one mechanism by which a promoter enables transcription to switch on and off during T-cell differentiation.