Grant: Project Grant

During the development of type 2 diabetes immune cell induced inflammation and metabolic stress induce insulin secreting beta-cells to lose their normal functionality. In part this is because the beta-cells have reduced levels or critical genes that help maintain them as fully functional cells. Restoring the levels of these critical genes can restore beta-cell functionality and is a possible therapeutic approach to treating type 2 diabetes. Despite this the mechanisms by which the levels of these factors become reduced in beta-cells during T2D progression is not clear. Our recent data shows that the structure of the chromatin around these genes plays a key role in regulating their expression, which dictates the levels they are present in in the cell. Specifically, we have found a unique type of modification that can occur to the chromatin can help reduce the variability of a genes expression in different cells, as genes with these modifications have reduced cell to cell variability than genes that do not have it. However, we find that in patients with T2D genes with these modifications become just as variably expressed as genes without these modifications. This not only results in an overall reduction in the levels of these genes in the beta-cells of T2D patients, but also means that some beta-cells exist in these patients with much lower levels than the average. We believe these cells become highly dysfunctional, and are a critical component of how T2D progresses. In this work we intend to determine how age and T2D increase transcriptional variability in beta-cells in both mouse models and in humans. We will assess whether these factors directly affect the chromatin modifications we believe control gene expression variability, and generate mouse models to understand the role these modifications play in maintaining normal gene expression. This work stands to generate significant novel insight into T2D progression, and may implicate novel therapeutic approaches.