Networking in a global world: Establishing functional connections between neural splicing regulators and their target transcripts

Calarco, John A.; Zhen, Mei; Blencowe, Benjamin J.

doi:10.1261/rna.2603911

Cited by 68 publications

(60 citation statements)

References 198 publications

(247 reference statements)

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“…Our data analysis identified a cluster of RBPs that are expressed in both brain and in human islets. This cluster includes members of the Elavl, Nova, and Rbfox families, which have been implicated in neuronal physiology and disease (28,(31)(32)(33)(34)(35). We found that Elavl4 and Nova2 are required for beta cell survival, and their depletion leads to activation of the intrinsic pathway of apoptosis.…”

Section: Discussionmentioning

confidence: 77%

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: Discussionmentioning

confidence: 77%

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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“…Individual tissues differ in their alternative splicing patterns due to different expression levels of key SFs, which determine such patterns through a combinatorial mode of action (Singh and Valcárcel 2005;Calarco et al 2011). For example, members of the arginine-serine rich (SR) proteins and heterogenous nuclear ribonucleoproteins (hnRNPs) compete for splice-site regulatory elements (Eperon et al 2000;Smith and Valcárcel 2000).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor-related Rac1b in colorectal cells

Gonçalves

Henriques

Pereira

et al. 2014

RNA

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The premessenger RNA of the majority of human genes can generate various transcripts through alternative splicing, and different tissues or disease states show specific patterns of splicing variants. These patterns depend on the relative concentrations of the splicing factors present in the cell nucleus, either as a consequence of their expression levels or of post-translational modifications, such as protein phosphorylation, which are determined by signal transduction pathways. Here, we analyzed the contribution of protein kinases to the regulation of alternative splicing variant Rac1b that is overexpressed in certain tumor types. In colorectal cells, we found that depletion of AKT2, AKT3, GSK3β, and SRPK1 significantly decreased endogenous Rac1b levels. Although knockdown of AKT2 and AKT3 affected only Rac1b protein levels suggesting a post-splicing effect, the depletion of GSK3β or SRPK1 decreased Rac1b alternative splicing, an effect mediated through changes in splicing factor SRSF1. In particular, the knockdown of SRPK1 or inhibition of its catalytic activity reduced phosphorylation and subsequent translocation of SRSF1 to the nucleus, limiting its availability to promote the inclusion of alternative exon 3b into the Rac1 pre-mRNA. Altogether, the data identify SRSF1 as a prime regulator of Rac1b expression in colorectal cells and provide further mechanistic insight into how the regulation of alternative splicing events by protein kinases can contribute to sustain tumor cell survival.

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“…Likewise, the pE1.3/3 and pE1.3/2/3 transcripts were most highly expressed in the kidney followed by the small intestine and then the liver, whereas the pE1.3/2/2.1/3 transcript was most highly expressed in the kidney followed by the liver, and was absent from the small intestine. Tissuespecific splicing, which incorporates up to eight different types of alternative splicing events (Wang et al 2008), has been extensively analyzed using microarrays in budding yeast and metazoans and using RNA-seq in human cell lines and tissues (Calarco et al 2011). Our data indicate an even more complicated level of mRNA splicing for the pPRLR gene, where the final mRNA composition not only depends on which tissue the transcript is expressed in but also on which first exon is transcribed.…”

Section: Figure 11mentioning

confidence: 89%

Comparative genomics reveals tissue-specific regulation of prolactin receptor gene expression

Schennink¹,

Trott²,

Manjarín³

et al. 2014

Journal of Molecular Endocrinology

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Prolactin (PRL), acting via the PRL receptor (PRLR), controls hundreds of biological processes across a range of species. Endocrine PRL elicits well-documented effects on target tissues such as the mammary glands and reproductive organs in addition to coordinating wholebody homeostasis during states such as lactation or adaptive responses to the environment. While changes in PRLR expression likely facilitates these tissue-specific responses to circulating PRL, the mechanisms regulating this regulation in non-rodent species has received limited attention. We performed a wide-scale analysis of PRLR 5 0 transcriptional regulation in pig tissues. Apart from the abundantly expressed and widely conserved exon 1, we identified alternative splicing of transcripts from an additional nine first exons of the porcine PRLR (pPRLR) gene. Notably, exon 1.5 transcripts were expressed most abundantly in the heart, while expression of exon 1.3-containing transcripts was greatest in the kidneys and small intestine. Expression of exon 1.3 mRNAs within the kidneys was most abundant in the renal cortex, and increased during gestation. A comparative analysis revealed a human homologue to exon 1.3, hE1 N2 , which was also principally transcribed in the kidneys and small intestines, and an exon hE1 N3 was only expressed in the kidneys of humans. Promoter alignment revealed conserved motifs within the proximal promoter upstream of exon 1.3, including putative binding sites for hepatocyte nuclear factor-1 and Sp1. Together, these results highlight the diverse, conserved and tissue-specific regulation of PRLR expression in the targets for PRL, which may function to coordinate complex physiological states such as lactation and osmoregulation.

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Networking in a global world: Establishing functional connections between neural splicing regulators and their target transcripts

Cited by 68 publications

References 198 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

Phosphorylation of SRSF1 by SRPK1 regulates alternative splicing of tumor-related Rac1b in colorectal cells

Comparative genomics reveals tissue-specific regulation of prolactin receptor gene expression

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