Novel Therapeutic Routes via X Chromsome Reactivation.

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We aim to discover novel therapeutic routes for X-linked diseases through XCR investigation. Although apparently homogenous, the inactive X chromosome (Xi) has a highly heterogenous chromatin with distinct domains characterised by different histone modifications (e.g. H3K27me3 and H3K9me3) and deposited by different chromatin modifying enzymes (e.g. PRC2, HP1, SmchD1 and TRIM28). This creates a combinatorial code that tunes X chromosome inactivation differently along the chromosome. We, therefore, aim to screen for epi-drugs and/or chromatin remodelling factors that are able to reactivate specific portions of the Xi chromosome. This will allow us to develop new therapies for those X linked-diseases such as neurodevelopmental (Rett syndrome) and neuromuscular diseases, and might be applied to sex-biased diseases.

This project is funded by an AFM telethon grant.

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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

Cantone I*. Reversal of X chromosome inactivation: lessons from pluripotent reprogramming of mouse and human somatic cells. J Transl Genet Genom 2017;1:1-14. doi:10.20517/jtgg.2017.19. Review.

Cantone I and Fisher AG. Human X chromosome inactivation and reactivation: implications for cell reprogramming and disease. Philos Trans R Soc Lond B Biol Sci. 2017 Nov 5;372(1733). pii: 20160358. doi: 10.1098/rstb.2016.0358. Review.

Cantone I* (corresponding author), Dharmalingam G, Chan YW, Kohler AC, Lenhard B, Merkenschlager M and Fisher AG. Allele-specific analysis of cell fusion-mediated pluripotent reprogramming reveals distinct and predictive susceptibilities of human X-linked genes to reactivation. Genome Biol. 2017 Jan 25;18(1):2. doi: 10.1186/s13059-016-1136-4.

Cantone I, Bagci H, Dormann D, Dharmalingam G, Nesterova T, Brockdorff N, Rougeulle C, Vallot C, Heard E, Chaligne R, Merkenschlager M, Fisher AG. Ordered chromatin changes and human X chromosome reactivation by cell fusion-mediated pluripotent reprogramming. Nat Commun. 2016 Aug 10;7:12354. doi: 10.1038/ncomms12354.

Cantone I, Fisher AG. Epigenetic programming and reprogramming during development. Nat Struct Mol Biol. 2013 Mar 5;20(3):282-9. doi: 10.1038/nsmb.2489.

Cantone I, Fisher AG. Unraveling epigenetic landscapes: the enigma of enhancers. Cell Stem Cell. 2011 Feb 4;8(2):128-9. doi: 10.1016/j.stem.2011.01.005.

Funded by Italian Foundation for Multiple Sclerosis, AFM Telethon and MUR