Re-organization of chromatin modifications in senescence controls genes involved in beta cell functionality

Cellular senescence, a permanent cell cycle arrest, is associated with aging and diseases including diabetes, obesity, atherosclerosis, cancer, osteoarthritis and Alzheimer’s disease. We recently found that p16^INK4a expression and cellular senescence influence pancreatic beta cell functionality, boosting glucose-stimulated-insulin-secretion. The role of beta cell senescence in diabetes is unclear. We wish to uncover how senescence modifies the organization of nuclear and chromatin structure in beta cells to reprogram gene expression and functionality. We documented gene expression pattern, genomic organization of heterochromatin marks as well as active chromatin marks after senescence induction in human model beta cell lines. Our analysis revealed upregulation of genes involved in cell cycle arrest, and also in insulin secretion, ribosomal biogenesis and protein translation in senescent beta cells. Interestingly, we observed upregulation of the activating H3k27ac modification on promoters and enhancers mostly in senescent beta cells. Many of these active promoters and enhancers overlap with known islet enhancer hubs (groups of active promoters, active enhancers, super-enhancers that form 3D hubs), which may impact insulin secretion. These data suggest underlying mechanisms that link chromatin organization and senescent beta cell functionality. Integration of gene expression and chromatin organization data could lead us to a deeper understanding of potential links between senescence and diabetes.