Diabetes affects ~10% of the adult population worldwide and its prevalence is rapidly increasing, representing a major health challenge. Diabetes is caused by dysfunction or loss of the insulin secreting beta cells of the pancreatic islets and the alteration of blood glucose levels. Despite the significant improvement of the life quality of diabetic patients during the last decades, there are currently no therapies to prevent or cure the disease. Thus, understanding how beta cells are generated, how they acquire their mature function and the ability to properly secrete insulin are major needs for the development of new therapies.
Extensive research in the field have uncovered the gene networks and signals that control the development of the different pancreatic endocrine cells. Moreover, the integration of genomics and genetics has revealed that genetic risk variants often alter the expression of key genes for beta cell function. Despite these remarkable advances, many aspects of gene regulation and function in pancreatic islets remain poorly understood. Among them, the roles of pre-mRNA alternative splicing (AS) have been largely unexplored. AS is a mechanism that allow single genes to produce multiple variants of its products (called RNAs and protein isoforms) by controlling the differential combination of gene pieces (introns and exons) into final molecules. This mechanism is a key generator of molecular diversity and plays pivotal roles in the development of organs and tissues, in the specialization of cell functions, and importantly, in several human diseases.
Thus, understanding how AS participates in beta cell differentiation and insulin secretory function, and its impact on glucose metabolism and diabetes can provide both basic and translatable knowledge for islet biology and for the development of novel therapies. Against this background, the goal of this project was to mechanistically and functionally characterize tissue-specific alternative splicing in endocrine pancreas, trying to answer the following questions: 1) Which are the master splicing regulators of AS in pancreas? 2) What is the impact of AS on beta cell development and secretory function? 3) Are endocrine-specific splicing programs deregulated in diabetes?
During the course of this project, we uncovered a conserved program of alternatively spliced microexons included specifically in islet cells. Our work revealed that islet microexons are regulated by the splicing factor SRRM3, and that dysregulation of the islet microexon program leads to defects in islet development and insulin secretion regulation, causing alteration of glucose homeostasis. Our findings thus provide novel insights into the transcriptional regulation of pancreatic endocrine cells development and function by alternative splicing.
