Transcriptional regulation of intestinal stem cell ageing

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.