Oestrogen Receptor-? binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer.

ABSTRACT: Oestrogen controls Foxp3 expression in regulatory T cells (Treg cells) via a mechanism thought to involve oestrogen receptor alpha (ER?), but the molecular basis and functional impact of ER? signalling in Treg cells remain unclear. We report that ER? ligand oestradiol (E2) is significantly increased in human cervical cancer (CxCa) tissues and tumour-infiltrating Treg cells (CD4+CD25hiCD127low), whereas blocking ER? with the antagonist ICI 182,780 abolishes FOXP3 expression and impairs the function of CxCa infiltrating Treg cells. Using a novel approach of co-immunoprecipitation with antibodies to E2 for capture, we identified binding of E2:ER? complexes to FOXP3 protein in CxCa-derived Treg cells. Chromatin immunoprecipitation analyses of male blood Treg cells revealed ER? occupancy at the FOXP3 promoter and conserved non-coding DNA elements 2 and 3. Accordingly, computational analyses of the enriched regions uncovered eight putative oestrogen response elements predicted to form a loop that can activate the FOXP3 promoter. Together, these data suggest that E2-mediated ER? signalling is critical for the sustenance of FOXP3 expression and Treg cell function in human CxCa via direct interaction of ER? with FOXP3 promoter. Overall, our work gives a molecular insight into ER? signalling and highlights a fundamental role of E2 in controlling human Treg cell physiology.

SUBMITTER: Adurthi S 

PROVIDER: S-EPMC5725534 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature