Understanding mechanisms of epigenetic instability in ageing and cancer

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In early embryonic development, XX female mammals will switch off nearly 1000 genes on one of their two X chromosomes (X chromosome inactivation, XCI) to balance gene expression with XY males. The silenced state of the inactive X (Xi) will be remembered by daughter cells and play a crucial role in cell physiology. Its dysregulation is involved in over 500 X-linked diseases including immune diseases, cancer and during ageing. XCI is essential to cell identity and physiology and the epigenetic instability of the Xi in female adult stem cells generates a huge obstacle for their applicability in regenerative medicine. The RNA Xist triggers XCI by recruiting to the Xi an array of epigenetic factors. This project will make use of embryonic stem cell differentiation and adult haematopoietic stem cells (HSCs) to explore how changes in the composition and protein-protein interactions (PPIs) of these RNA-guided assemblies lead to a heritable silent state or result in epigenetic instability and XCR in ageing or cancer. This research is important because it will provide mechanistic insights on this fundamental process of life, how it goes wrong in ageing or disease and shed light on principles of RNA-guided gene-regulatory events using the prototype RNA, Xist.