17ß-estradiol induces changes in histone modifications at cell type-specific genomic regions involved in Th17/Treg cell plasticity

Estrogens possess a key physiological role typically associated with the reproductive system, however they have an impact also on several other tissues and structures, including the immune system. Indeed, estrogens act on the immune response influencing the disease outcome or susceptibility. However, the cross-talk between these hormones and the immune system still represents a little explored field. In this work, we investigated at the epigenetic level the estrogens effect on Th17/Treg cell plasticity. In a previous study from our laboratory, we described a pregnancy-related epigenetic signature in T cells deriving from multiple sclerosis patients and in in vitro polarized Th17 cells upon 17β-estradiol treatment. The definition of such epigenetic pattern started from an integrative genome-wide data analysis that helped us to select cell-type specific regulatory regions (CSRs) that were under the estrogen receptor alpha (ERα) control and linked with core transcription factors (TFs) inside Th17 and Treg cell regulatory networks. Herein, we performed in vitro time course experiments on Peripheral Blood Mononuclear Cells (PBMCs) from human healthy donors imposing Th17 cell polarizing conditions in the presence or absence of 17β-estradiol (E2) in pregnancy concentrations (35 ng/ml), and we looked for differences in histone marks regarding a novel set of such CSRs and in the expression of both the transcript and the protein originating from the related TF genes. Among the tested regions, we found that E2 particularly inhibited the transcription of MAF and SATB1 genes. Indeed, at the CSRs associated with these two loci, H3K4me3 and H3K27ac histone modifications increased upon Th17 cell polarization and decreased after E2 treatment, suggesting that E2 may orchestrate CD4+ T cell identity through chromatin remodelling. Furthermore, we highlighted different genomic regions regulating critical TF-coding genes as potential candidates for ERα-mediated epigenetic events. Our results show that cell type-specific regulatory regions may be used as putative biomarkers to monitor immune system adaptation as well as the progression of many autoimmune diseases, such as multiple sclerosis.