Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival
(2017) In Journal of Biological Chemistry 292(8). p.3466-3480- 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 neuronal-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... (More)
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 neuronal-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 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, while 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.
(Less)
- author
- organization
- publishing date
- 2017-01-11
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 292
- issue
- 8
- pages
- 3466 - 3480
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- scopus:85013758218
- wos:000395538800035
- pmid:28077579
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M116.748335
- language
- English
- LU publication?
- yes
- id
- 96b1a93d-d98f-4b9b-a6c6-e38eecb542c7
- date added to LUP
- 2017-01-27 15:46:59
- date last changed
- 2024-08-10 03:55:37
@article{96b1a93d-d98f-4b9b-a6c6-e38eecb542c7, abstract = {{<p>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 neuronal-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 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, while 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.</p>}}, author = {{Juan-Mateu, Jon Agraves and Rech, Tatiana H and Villate, Olatz and Lizarraga-Mollinedo, Esther and Wendt, Anna and Turatsinze, Jean-Valery and Brondani, Leticia A and Nardelli, Tarlliza R and Nogueira, Tatiane C and Esguerra, Jonathan and Alvelos, Maria In Ecircs and Marchetti, Piero and Eliasson, Lena and Eizirik, D Eacutecio L}}, issn = {{1083-351X}}, language = {{eng}}, month = {{01}}, number = {{8}}, pages = {{3466--3480}}, publisher = {{American Society for Biochemistry and Molecular Biology}}, series = {{Journal of Biological Chemistry}}, title = {{Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival}}, url = {{http://dx.doi.org/10.1074/jbc.M116.748335}}, doi = {{10.1074/jbc.M116.748335}}, volume = {{292}}, year = {{2017}}, }