Epigenetics of Sex Biased diseases and X chromosome reactivation (XCR)

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We investigate XCR as a novel mechanism for sex-biased diseases (e.g. cancer, autoimmunity, neurological diseases). Loss of X inactivation can potentially 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. XIST RNA cannot, in fact, properly localize onto the Xi in resting lymphocytes. This leads to expression of X linked genes related with immune functions (i.e. TLR7, CD40L and CXCR3) from the inactive X chromosome (Xi). Notably, in physiological conditions XIST goes back to coat the Xi upon antigen stimulus. If an autoimmune disease or reaction is in place, XIST cannot properly re-localize upon cell activation and Xi gene silencing might be permanently compromised. This might, indeed, lead to Xi gene expression unbalance and might be a driving cause of the observed sex bias in autoimmunity (women are more affected by autoimmune diseases than men). In our lab, we investigate a T-cell mediated autoimmune disease: Multiple Sclerosis. We aim at understanding whether incomplete inactivation of X chromosome (XCI) is involved in the MS sex bias by using single-cell genomics and imaging approaches. This project addresses the hypothesis that X chromosome reactivation (XCR) mediates the higher incidence of MS in females versus males by leading to the overexpression of X-linked autoimmunity-mediating genes.

This project is funded by the Italian Foundation for Multiple Sclerosis (FISM) and the Ministry of University and Reasearch (PRIN - MUR).

Spaziano A and Cantone I*. X-chromosome reactivation: a concise review. Biochem Soc Trans. 2021 Dec 17;49(6):2797-2805. doi: 10.1042/BST20210777.

Credendino SC, Neumayer C & Cantone I*. Genetic and Epigenetic of Sex Bias: insights from human cancer and autoimmunity. Trends in Genetics 2020 Sep;36(9):650-663. doi: 10.1016/j.tig.2020.06.016. Review