Dissecting genetic regulatory mechanisms in human pancreatic islets to gain insights into type 2 diabetes pathophysiology

Abstract

Diabetes mellitus is a heterogeneous group of metabolic diseases characterized by impaired blood glucose homeostasis that affects more than 415 million people worldwide and is a leading cause of mortality. The most prevalent form of diabetes is Type 2 Diabetes (T2D) that accounts for 90% of diabetes cases. An interplay of environmental and genetic risk factors contributes to etiology of T2D via a progressive loss of pancreatic beta cell function coupled with insulin resistance. Genome Wide Association Studies (GWAS) identified more than 400 independent genetic loci associated with T2D risk, although the molecular mechanisms underlying these genetic signals remain poorly understood. A comprehensive understanding of gene regulation in human pancreatic islets and identifying the role of T2D risk variants on different components of gene regulation will enlighten our insights into T2D etiology. In this work, we performed an in-depth characterization of human pancreatic islets transcriptional regulatory elements, attaining a greater granularity at transcriptional enhancers. We further identified glucose responsive enhancers which regulate glucose-dependent gene expression programs via three-dimensional chromatin interactions. This allowed us to gain insights into human islet transcriptional gene regulation and how glucose, a primary physiological stimulant of pancreatic islets, modulates human islet genome function. We also generated comprehensive transcriptome annotations in human islets using short- and long-read sequencing data along with accurate maps of transcriptional start sites. This revealed islet-specific promoters, transcript isoforms and novel coding sequences. This underscored the importance of generating transcript models in disease relevant tissue to progress in the understanding of gene regulation. Finally, these parallel efforts allowed us to create pioneer maps of genetic effects on human alternative splicing that revealed for the first time the noteworthy contribution of human islet mRNA splicing to T2D pathophysiology. These results have thus the potential to blossom in the discovery of novel T2D drug targets.