Transcriptional regulation of intestinal stem cell ageing

背景肠道功能下降是老年人健康状况不佳的一个重要因素。肠干细胞（ISCs）受到严格调控，以平衡分化与增殖，并在整个成年期维持组织。然而，在老化的肠道中，这种平衡丧失，导致与死亡相关的发育不良和组织功能下降。最终，干细胞命运的变化在基因表达水平上协调，这取决于局部染色质状态。几种染色质组分和修饰剂已被证明在稳态ISC维持、增殖和分化中起重要作用。然而，对肠道干细胞中基因表达的调控如何随年龄变化缺乏全面的了解。实验室正在进行的工作是使用靶向DamID来分析ISC中基因表达和染色质状态随年龄的变化。目标。本项目将功能性地研究果蝇ISCs中随年龄变化表达的转录因子和染色质调节因子。重要性ISCs的平衡增殖和分化对于整个生命中的稳态组织维持和修复至关重要。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。该项目将提高我们对干细胞在转录控制和染色质状态水平上如何被错误调节的理解。它将使我们能够确定调控原则和基因，这些原则和基因可以作为干预的目标，以保持组织功能随年龄的增长。

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.