Abstract
Increasing evidence supports the anti-inflammatory role of estrogens in Multiple Sclerosis (MS), originating from the observation of reduction in relapse rates among women with MS during pregnancy, but the molecular mechanisms are still not completely understood. Using an integrative data analysis, we identified T helper (Th) 17 and T regulatory (Treg) cell-type-specific regulatory regions (CSR) regulated by estrogen receptor alpha (ERα). These CSRs were validated in polarized Th17 from healthy donors (HD) and in peripheral blood mononuclear cells, Th17 and Treg cells from relapsing remitting (RR) MS patients and HD during pregnancy. 17β-estradiol induces active histone marks enrichment at Forkhead Box P3 (FOXP3)-CSRs and repressive histone marks enrichment at RAR related orphan receptor C (RORC)-CSRs in polarized Th17 cells. A disease-associated epigenetic profile was found in RRMS patients during pregnancy, suggesting a FOXP3 positive regulation and a RORC negative regulation in the third trimester of pregnancy. Altogether, these data indicate that estrogens act as immunomodulatory factors on the epigenomes of CD4+ T cells in RRMS; the identified CSRs may represent potential biomarkers for monitoring disease progression or new potential therapeutic targets.
Highlights
Multiple Sclerosis (MS) is an autoimmune disease characterized by chronic inflammation of the central nervous system (CNS) affecting 2.5 million people worldwide, with a female/male sex ratio of 3:1 [1, 2]
Since we were interested in the identification of putative genomic targets of estrogens signaling in Th17 and T regulatory (Treg) cells, ERα modulated chromatin regulatory hubs were identified by using an integrative analysis of epigenomic and transcriptomic data
We designed a computational approach composed of four consecutive Generation Sequencing (NGS) data integration steps: (i) Super Enhancers (SEs) prediction in CD4+ T cell subtypes, (ii) chromatin states analysis for identification of active regulatory regions, (iii) overlap between these regions and SEs detected in Th17 and Treg cells, (iv) reconstruction of a core TFs regulatory network of Th17 and Treg cells and identification of putative ERα targets (Figure 1A)
Summary
Multiple Sclerosis (MS) is an autoimmune disease characterized by chronic inflammation of the central nervous system (CNS) affecting 2.5 million people worldwide, with a female/male sex ratio of 3:1 [1, 2]. Pro-inflammatory T helper (Th) 17 cells are required for the pathogenesis of MS [3, 4] and its mouse model, the experimental autoimmune encephalomyelitis (EAE), whereas CD4+Foxp3+ regulatory T cells (Treg), crucial for preventing autoimmunity, are defective in numbers and functions [5]. Epigenetic Signature of MS Pregnancy trimester when they peak and the most pronounced decrease in the relapse rate occurs [6]. This potent, short-term beneficial effect of pregnancy is followed by a temporary rebound of disease activity post-partum, probably due to the fall of estrogen serum concentration [7]. In MS patients, the protective effect of estrogens has been reported in a pivotal trial [16, 17] and currently, large placebo-controlled clinical trials of estrogen therapy in MS are still ongoing [18]
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