Il controllo epigenetico dell'equilibrio dei Treg e dei Th17 mediato dal recettore degli estrogeni alpha

Estrogen Receptor-alpha (ERα) is a key player transcription factor in breast cancer, however it has a role in other tissues, such as the immune system. Estrogen has an immune-modulatory effect, but little is known about the molecular mechanisms that underlie immune-modulation. One mechanism by which estrogen exerts its function is the inhibition of pro-inflammatory Th17 cells differentiation and the stimulation of proliferation of Treg cells. Th17 and Treg cells have an opposite role in the immune response and the adaptation of T cells to the environment depends on chromatin remodeling that controls cell identity. Chromatin remodeling regulates T cell differentiation acting on the main genomic regulatory regions that control lineage-specific transcription factors. We focused our attention on FoxP3 and RORC, respectively master transcription factors for Treg and Th17 cells. To identify the cell-type- specific regulatory genomic regions on FoxP3 and RORC loci, we used integrative analysis based on epigenetic-modifications experiments with ChIP-Seq. In particular, we selected clusters of enhancers, named Super-enhancers (SEs), using active enhancer mark, H3K27Ac ChIP-Seq datasets. ERα binding on SE are predicted by bioinformatic tool (JASPAR Core 9), that finds ERα-binding consensus sequence, Estrogen Responsive Element (ERE) enrichment. We tested the promoter and the selected genomic regulatory regions for FoxP3 and RORC loci on PBMCs and purified Th17 and Treg cells upon 17β-estradiol (E2) treatment. We observed that ERα binds on RORC and FoxP3 promoters and on genomic regulatory regions both in PBMCs and purified Th17 and Treg cells. E2 induces H3K4me3, an active marker, enrichment on FoxP3- regulated SE regions and H3K27me3, repressive mark, enrichment on RORC-regulated SE regions in Th17 cells suggesting that Th17 cells may shift to regulatory T cells. Interestingly, we obtained the same results in E2- treated PBMC during time course of Th17 cell differentiation; an experimental condition that simulates the Th17 cell activation during inflammation. Altogether our data suggest that ERα may play a central role for chromatin remodeling and for the regulation of Th17/Treg cells balance. Moreover the identification of these specific genomic regions that regulate cell identity and ERα role in immune-modulation may allow the discovery of new specific potential drug targets or epigenomics biomarkers to monitor several diseases, such as Multiple Sclerosis.