Hosted by the MRC Integrative Epidemiology Unit

https://www.bristol.ac.uk/integrative-epidemiology/seminars/mendel_200/mendel-at-200-webinars/

Abstract: In female mammals, one of the two X chromosomes becomes inactivated during early development in order to achieve X-chromosome dosage compensation between the sexes. X-chromosome inactivation (XCI) is usually initiated at random in eutherian mammals and the choice of inactive X is then stably propagated in somatic tissues, leading to clonal populations of cells expressing either the maternal or the paternal X. Thus females are cellular mosaics for X-linked allelic gene expression and this can lead to phenotypic variation both within and between individuals. There is also an increasing realization that the inactive X chromosome contributes to male-female differences in physiology and disease. Indeed, a significant proportion of X-linked genes can escape XCI and the increased dosage of proteins encoded by these genes can lead to genome-wide differences, influencing a wide variety of processes including cell differentiation and metabolism. My lab is interested in understanding how X-chromosome inactivation (XCI) is established and maintained, and how some genes escape XCI mainly using mouse as a model. Establishment of XCI involves the non-coding Xist RNA that coats the chromosome it is expressed from and triggers gene silencing as well as chromatin changes and 3D re-organisation of the X. Our recent work has focused on the role of Xist RNA’s partners in mediating these changes, in particular the SPEN protein, which acts as a platform for multiple factors acting on transcription, chromatin and RNA metabolism. Although most X-linked genes are sensitive to Xist RNA and SPEN in mouse XCI, different genes along the X show very different timing and extent of gene silencing and we are exploring the genetic and epigenetic basis for this differential gene silencing. This should provide important insights into precise mechanisms of transcriptional repression. We are also interested in understanding how some genes along the X chromosome display varying extents of escape from XCI and how this may be linked to sex-biased disorders. Our recent work exploring the process of XCI and the implications of variable expression from the inactive X chromosome will be presented.  

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