Every cell in a woman’s body must silence one of its two X chromosomes to avoid a toxic overdose of genetic instructions. This process, called X inactivation, is orchestrated by a long non-coding RNA molecule named Xist, which coats the chosen chromosome and shuts it down. Despite decades of study, researchers still do not understand exactly how Xist triggers this wholesale silencing, how the silenced state is locked in and inherited as cells divide, or how the enzymes that add chemical tags to the DNA are recruited to the right places. This project will answer those three fundamental questions. The work is primarily curiosity-driven fundamental science, probing a core mechanism of gene regulation in mammals. However, the same molecular machinery that silences an X chromosome can go awry in disease. Mutations in the genes that stabilise the inactive state are linked to facioscapulohumeral muscular dystrophy, a rare form of dwarfism called ICF syndrome, and certain cancers. A clearer picture of how Xist and its partners work could eventually explain why these diseases arise and point toward targets for intervention.
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X inactivation is the mechanism that has evolved in mammals to equalise gene dosage on the X chromosome in XX females relative to XY males. Work in the 1990s established that the master regulator for chromosome silencing is a large non-coding (nc)RNA, designated Xist (X inactive Specific Transcript). Xist RNA is transcribed from the inactive X (Xi) elect and coats the entire chromosome territory in cis. This in turn triggers chromosome wide transcriptional silencing and the establishment of a s table and heritable inactive chromatin state. X inactivation provides a powerful model system for understanding the function of ncRNAs and the role of epigenetic mechanisms, for example DNA methylation and chromatin modification, in genome regulation during cellular differentiation and development. Central questions in the field that this proposal will tackle are: 1. How does Xist RNA instigate chromosome wide silencing? 2. What are the mechanisms that confer stability and heritability of the inactive state, and how do they link to the primary silencing mechanism and to one another? 3. How are de novo DNA methyltransferases targeted in X inactivation and at other genomic sites? In addition to answering basic research questions this work will have relevance to understanding disease states, specifically epigenome regulation in cancer, chromosome instability and craniofacial abnormalities (ICF) syndrome, linked to mutations in the Dnmt3b gene, and Facioscapulohumeral dystr opy (FSHD type I and II) linked to mutations in SMCHD1.
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