Nova1 is a master regulator of alternative splicing in pancreatic beta cells

Villate, Olatz; Turatsinze, Jean Valéry; Mascali, Loriana; Grieco, Fabio Arturo; Nogueira, Tatiane C; Cunha, Daniel Andrade Da; Nardelli, Tarlliza Romanna; Sammeth, Michael; Salunkhe, Vishal Va; Esguerra, Jonathan L.S.; Eliasson, Lena; Marselli, Lorella; Marchetti, Piero; Eizirik, Décio L.

doi:10.1093/nar/gku861

Cited by 72 publications

(88 citation statements)

References 81 publications

(119 reference statements)

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“…We have previously shown that Nova1 controls beta cell function and survival by regulating genes involved in exocytosis, apoptosis, insulin receptor signaling, splicing, and transcription (27). Here we provide additional data showing that Nova2 depletion impairs beta cell survival but not insulin secretion.…”

Section: Role Of Neuron-enriched Rna-binding Proteins In Beta Cellssupporting

confidence: 58%

“…Here we provide additional data showing that Nova2 depletion impairs beta cell survival but not insulin secretion. Increased apoptosis by Nova2 KD may be secondary to up-regulation of the FoxO3A transcription factor and pro-apoptotic protein Bim, as observed previously in Nova1 KD (27). The absence of insulin secretion defects may be explained by differences in targets genes between the Nova paralogs.…”

Section: Role Of Neuron-enriched Rna-binding Proteins In Beta Cellssupporting

confidence: 54%

“…Although the role of AS in the development of diabetes remains to be clarified, recent studies from our group indicate that AS alterations induced by both inflammation and disease susceptibility genes contribute to beta cell dysfunction and death (24 -26). Furthermore, we found that the "neuron-specific" splicing factor Nova1 is expressed in beta cells (24) and regulates AS of genes involved in exocytosis and apoptosis (27).…”

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confidence: 97%

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Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival

Juan-Mateu

Rech

Villate

et al. 2017

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinPancreatic 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-␤H1 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.Insulin-secreting pancreatic beta cells share many phenotypic traits with neurons. Similarities range from an analogous physiology and function to similar development and gene expression (1). Beta cells release insulin using a similar exocytotic machinery as used by neurons to release neurotransmitters. Indeed, insulin is stored and secreted using scaffolding proteins and synaptic-like vesicles similar to neuronal cells (2-4), and like neurons, beta cells are able to generate action potentials in response to different stimuli (5). Despite having different embryonic origins (6, 7), global gene expression and active chromatin marks of beta cells are closer to neural tissues than to any other tissue, including other pancreatic cells (8). Neurons are phylogenetically older than beta cells, and in some primitive organisms neurons express insulin and regulate circulating glucose levels (9, 10). Taken together, these findings suggest that beta cells have evolved into specialized insulinsecretory cells by adopting, at least in part, neuronal transcription programs (1). Supporting this hypothesis, both neurons and beta cells lose the expression of the transcriptional repressor element-1 silencing transcription factor (REST) 5 during differentiation (11). REST is expressed in most non-neuronal cells and acts as a master negative regula...

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Section: Role Of Neuron-enriched Rna-binding Proteins In Beta Cellssupporting

confidence: 58%

Section: Role Of Neuron-enriched Rna-binding Proteins In Beta Cellssupporting

confidence: 54%

mentioning

confidence: 97%

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Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival

Juan-Mateu

Rech

Villate

et al. 2017

Journal of Biological Chemistry

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“…To further investigate the role of individual splicing factors in the regulation of β cell function and survival, we studied the ‘neuron-specific’ RBP NOVA1 using siRNA silencing coupled with RNA-seq (12) (Fig. 5).…”

Section: β Cell Death In Type 1 Diabetes and The Role Of Asmentioning

confidence: 99%

“…These splicing regulators are RNA-binding proteins (RBPs) of the serine/arginine (SR)-rich proteins and heterogeneous nuclear RNPs (hnRNP) families, as well as other cell-, stage- or tissue-specific proteins such as the NOVA, RBFOX, CELF or MBLN families. These families establish the splicing code and determine in a combinatorial fashion which splice site is selected in specific tissues (for instance, NOVA1 is only expressed in brain and pancreatic β cells) (11, 12, 13, 14). The regulation of AS is accomplished by the relative expression levels of the different RBPs, determining how efficiently different splice sites are used to generate specific mRNA isoforms in different cells and tissues.…”

Section: Introductionmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research

Juan-Mateu

Villate

Eizirik

2016

European Journal of Endocrinology

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Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic β cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target β cells, but the intracellular signals that decide β cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic β cells contribute to the pathogenesis of T1D. Splicing switches in Tcells and in lymph node stromal cells are involved in the modulation of the immune response against β cells, while β cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate β cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in β cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy.

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Global analysis of RNA–protein interactions in TNF‐α induced alternative splicing in metabolic disorders

et al. 2021

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In this report, using the database of RNA-binding protein specificities (RBPDB) and our previously published RNA-seq data, we analyzed the interactions between RNA and RNA-binding proteins to decipher the role of alternative splicing in metabolic disorders induced by TNF-a. We identified 13 395 unique RNA-RBP interactions, including 385 unique RNA motifs and 35 RBPs, some of which (including MBNL-1 and 3, ZFP36, ZRANB2, and SNRPA) are transcriptionally regulated by TNF-a. In addition to some previously reported RBPs, such as RBMX and HuR/ELAVL1, we found a few novel RBPs, such as ZRANB2 and SNRPA, to be involved in the regulation of metabolic syndrome-associated genes that contain an enrichment of tetrameric RNA sequences (AUUU). Taken together, this study paves the way for novel RNA-protein interaction-based therapeutics for treating metabolic syndromes.

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Nova1 is a master regulator of alternative splicing in pancreatic beta cells

Cited by 72 publications

References 81 publications

Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival

Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival

MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research

Global analysis of RNA–protein interactions in TNF‐α induced alternative splicing in metabolic disorders

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