Understanding mechanisms of epigenetic instability in ageing and cancer

了解衰老和癌症中表观遗传不稳定性的机制

• 批准号: 2882189
• 金额: --
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2882189
• 关键词: Understanding; mechanisms; epigenetic; instability; ageing

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.

在胚胎发育早期，XX雌性哺乳动物将关闭其两条X染色体之一上的近1000个基因（X染色体失活，XCI），以平衡XY雄性的基因表达。失活的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。它的失调涉及500多种X连锁疾病，包括免疫疾病，癌症和衰老。XCI对于细胞身份和生理学是必不可少的，并且Xi在女性成体干细胞中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来触发XCI。该项目将利用胚胎干细胞分化和成体造血干细胞（HSC）来探索这些RNA引导的组装体的组成和蛋白质-蛋白质相互作用（PPI）的变化如何导致可遗传的沉默状态或导致衰老或癌症中的表观遗传不稳定性和XCR。这项研究很重要，因为它将为生命的这一基本过程、它在衰老或疾病中如何出错提供机械见解，并揭示使用原型RNA Xist的RNA引导基因调节事件的原理。