X-chromosome inactivation (XCI) represents a classic example of epigenetics in mammals. In this process, one of the two X chromosomes in females is converted from an active into a clonally heritable, inactive, state during early embryonic development, to ensure dosage compensation between the sexes. This process is also remarkable in that an entire chromosome is silenced while its homologue, present in the same nucleus, remains active. Thus, in addition to being an epigenetics paradigm, XCI also represents a powerful model for monoallelic gene expression and could provide important insights into the mechanisms underlying other examples of random, monoallelic regulation. The key locus underlying the initiation of XCI is the X-inactivation centre (Xic). The Xic ensures the induction and monoallelic expression of a non-coding RNA (Xist) that is responsible for triggering chromosomal silencing in cis during development. We would like to understand the mechanisms underlying the Xic's functions and define whether other, Xic-like loci exist in the genome. Once XCI is established, the inactive state is initially reversible but becomes progressively locked in as development proceeds due to numerous epigenetic marks such as DNA methylation and histone modifications, as well as nuclear compartmentalization and asynchronous replication. In the proposed program, we will exploit our expertise in XCI to develop new lines of research and use novel technologies to investigate monoallelic gene expression, nuclear organization and epigenetics during development. Our main objectives are (1) to understand how monoallelic expression states are established and maintained during early development and (2) to assess how chromosome dynamics and nuclear architecture can impact on these states.
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