Abstract
Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuron-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function, and disease. The role of alternative splicing in beta cells remains unclear, but recent data indicate that splicing alterations modulated by both inflammation and susceptibility genes for diabetes contribute to beta cell dysfunction and death. Here we used RNA sequencing to compare the expression of splicing-regulatory RNA-binding proteins in human islets, brain, and other human tissues, and we identified a cluster of splicing regulators that are expressed in both beta cells and brain. Four of them, namely Elavl4, Nova2, Rbox1, and Rbfox2, were selected for subsequent functional studies in insulin-producing rat INS-1E, human EndoC-βH1 cells, and in primary rat beta cells. Silencing of Elavl4 and Nova2 increased beta cell apoptosis, whereas silencing of Rbfox1 and Rbfox2 increased insulin content and secretion. Interestingly, Rbfox1 silencing modulates the splicing of the actin-remodeling protein gelsolin, increasing gelsolin expression and leading to faster glucose-induced actin depolymerization and increased insulin release. Taken together, these findings indicate that beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival, and their dysfunction may contribute to the loss of functional beta cell mass in diabetes.
Highlights
Pancreatic beta cell failure is the central event leading to diabetes
We examined the expression of splicing-regulatory RNA-binding proteins (RBPs) in pancreatic islets, brain, and other human tissues and detected a group of splicing regulators that are preferentially expressed in human islets and brain
Some brain-expressed RBPs clustered together with the five human islet preparations evaluated, and we identified a group of RBPs that are relatively highly expressed in both human islets and brain (Fig. 1A, yellow square)
Summary
Pancreatic Beta Cells Express Neuron-enriched RNA-binding Proteins—We used a previous RNA sequencing dataset of human islets [24] and the Illumina BodyMap 2.0 (GEO: GSE30611) to compare the expression of 118 splicing-regulatory RBPs between human islets and 16 other tissues. Double KD of Rbfox and gelsolin prevented the increase in insulin secretion detected after Rbfox KD alone (Fig. 9C), indicating that the observed phenotype is probably secondary to alterations in cytoskeleton remodeling. Rbfox1-KD cells displayed a faster glucose-induced actin depolymerization when compared with control cells (Fig. 10, B and C) These differences were more pronounced with siFOX1#2, the siRNA inducing higher levels of Rbfox KD and a more extreme phenotype, and were prevented by gelsolin silencing (Fig. 10, A–C). These findings indicate that the observed increase in insulin secretion following Rbfox KD is secondary to increased gelsolin expression and consequent enhanced actin depolymerization
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