Epigenetics of Sex Biased diseases and XCR

We investigate XCR as a novel mechanism for sex-biased diseases (e.g. cancer, autoimmunity, neurological diseases). Loss of inactivation can potentially lead to generate new functions or dysfunctions in a tissue. This might commonly result from the delocalization of XIST from the Xi territory at every cell cycle, but can also occur in cell types with a peculiar chromatin structure, i.e. lymphocytes. I have previously shown that XIST cannot properly localize onto the Xi in resting Lymphocytes (i.e. B and T). This leads to minor expression of X linked genes related with immune functions (i.e. TLR7, CD40L and CXCR3) from the inactive chromosome. Interestingly, in physiological conditions XIST goes back to coat the Xi upon antigen stimulus whereas if an autoimmune disease or reaction is in place this does not happen and Xi gene expression is permanently compromised. This has starting to be shown for systemic lupus erithemathousus and suggests that epigenetic relaxation of X chromosome inactivation in immune cells might predisposes Xi genes to reactivation leading to Xi gene expression unbalance and sec bias in autoimmunity. Here, we will investigate another T-cell mediated autoimmune disease: Multiple Sclerosis. We aim at understanding whether incomplete inactivation of X chromosome (XCI) is involved in MS gender bias. The project addresses the hypothesis of sex-bais by human X chromosome inactivation and is particularly relevant for translational research as an increase in the MS sex bias has been observed over the last decades with a raising number of affected women.

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