Understanding mechanisms of epigenetic instability in ageing and cancer

在胚胎发育早期，XX雌性哺乳动物会关闭两条X染色体中的一条上的近1000个基因（X染色体失活，XCI），以平衡与XY雄性的基因表达。失活X （Xi）的沉默状态将被子细胞记住，并在细胞生理学中起着至关重要的作用。它的失调与500多种与x相关的疾病有关，包括免疫疾病、癌症和衰老。XCI对细胞身份和生理至关重要，而雌性成体干细胞中XCI的表观遗传不稳定性对其在再生医学中的应用产生了巨大的障碍。RNA Xist通过招募一系列表观遗传因子触发XCI。该项目将利用胚胎干细胞分化和成人造血干细胞（hsc）来探索这些rna引导的组件的组成和蛋白质-蛋白质相互作用（PPIs）的变化如何导致遗传沉默状态或导致表观遗传不稳定和衰老或癌症中的XCR。这项研究很重要，因为它将提供关于生命这一基本过程的机制见解，它是如何在衰老或疾病中出错的，并阐明使用原型RNA Xist的RNA引导的基因调控事件的原理。

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.