Wednesday, April 24, 2024
4/24/2024
Abstract Type 2 diabetes (T2D) is a complex disease that arises from a combination of genetic and environmental factors. Previous genome wide association studies (GWAS) of T2D have identified over 600 independent genetic signals, but most fall within non-coding regions of the genome, which makes identifying underlying mechanisms difficult. These signals can be cell-type specific, which adds another layer of complexity to nominating mechanisms. Recent work within the lab has identified skeletal muscle cell-type specific genetic regulators by investigating single-nucleus resolution chromatin structure across hundreds of samples. We observed several T2D GWAS signals colocalize specifically with mesenchymal stem cell (MSC) genetic regulators of chromatin structure, which represents a precursor cell stage that may reflect an early indicator of disease predisposition. Previous work within the lab has identified an ARL15 intronic T2D GWAS signal that is specific to MSCs. Chromatin looping analyses showed that this genetic regulatory region interacts with the follistatin (FST) promoter ~500kb away. The protein follistatin promotes muscle growth and affects insulin resistance by binding activin A and preventing it from inhibiting the mTOR pathway. Up-regulation of the FST pathway has been linked to increased T2D risk and impacts adipocyte differentiation. Follistatin is responsive to environmental stimulation, including inflammation, insulin, and glucose levels. These observations provide strong evidence that exploring the stimulatory state specific genetics of MSC chromatin structure, especially at FST and related pathway genes, will have implications for T2D. As a result, I am interested in studying the state-specific contexts which may influence T2D predisposition in MSCs, especially the state-specific genetic regulatory landscape of FST. Previous studies have shown that cellular state influences the genetic regulation of gene expression, where cells in a basal state display a “primed” chromatin conformation at response- specific differentially regulated genes. This primed state reflected a basal chromatin configuration that enabled the response-specific gene expression change. Therefore, the genetic signals of gene regulation vary across cell states within a cell type. To begin to investigate this within T2D, I will generate MSCs, induce different stimulatory states, and generate gene expression and chromatin structure data to establish genome-wide maps of FST pathway genes. Finally, I will investigate the FST gene pathway and select loci for validation with a novel inducible CRISPRi/a platform. Overall, I will generate MSC maps in different stimulatory states and use a multi-omics approach to compare the genetic control of gene expression and chromatin structure, focusing on the gene FST and related pathway genes, with the goal of nominating mechanisms at T2D GWAS signals.
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