Transcriptional regulation of intestinal stem cell ageing

背景资料。肠功能下降是老年人健康状况不佳的重要原因。肠道干细胞(ISCs)受到严格的调控，以平衡分化和增殖，并在成年后维持组织。然而，在老化的肠道中，这种平衡会失去，导致与死亡相关的发育不良和组织功能下降。最终，干细胞命运的变化是在基因表达水平上协调的，这取决于局部的染色质状态。一些染色质成分和修饰物已被证明在体内平衡ISC的维持、增殖和分化中发挥重要作用。然而，对肠道干细胞中基因表达如何随年龄变化的调控缺乏全面的了解。该实验室正在进行的工作是使用靶向DAMID来分析ISCs中基因表达和染色质状态随年龄的变化。瞄准。这个项目将对转录因子和染色质调节因子进行功能性表征，这些转录因子和染色质调节因子在果蝇ISCs中的表达随着年龄的变化而变化。重要性。ISCs的平衡增殖和分化对于维持体内平衡的组织和终生修复至关重要。干细胞的过度增殖和错误调节与年龄相关的组织功能下降有关。这个项目将提高我们对干细胞如何在转录控制和染色质状态水平上变得错误调节的理解。这将使我们能够确定调控原则和可以作为干预目标的基因，以随着年龄的增长保持组织功能。

BACKGROUND. Declining intestinal function is an important contributor to poor health in ageing. Intestinal stem cells (ISCs) are tightly regulated to balance differentiation with proliferation and maintain the tissue throughout adult life. However, in the ageing intestine this balance is lost resulting in the dysplasia and declining tissue function that are associated with mortality. Ultimately changes in stem cell fate are coordinated at the level of gene expression, which depends on local chromatin states. Several chromatin components and modifiers have been shown to play important roles in homeostatic ISC maintenance, proliferation and differentiation. However, a comprehensive understanding of how regulation of gene expression changes in intestinal stem cells with age is lacking. Ongoing work in the lab is using targeted DamID to profile changes in gene expression and chromatin states in ISCs with age. AIM. This project will functionally characterise transcription factors and chromatin regulators that change expression in Drosophila ISCs with age. IMPORTANCE. The balanced proliferation and differentiation of ISCs is critical for homeostatic tissue maintenance and repair throughout life. Hyper-proliferation and mis-regulation of stem cells is associated with age- related decline in tissue function. This project will improve our understanding of how stem cells become mis-regulated at the level of transcriptional control and chromatin states. It will allow us to identify both regulatory principles and genes that could be targeted for intervention to maintain tissue function with age.