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Alternative Splicing and 174:5 R225–R238 Review Others Diabetes J Juan-Mateu, O Villate and Alternative splicing and 174:5 R225–R238 Review others diabetes MECHANISMS IN ENDOCRINOLOGY Alternative splicing: the new frontier in diabetes research Jona` s Juan-Mateu*, Olatz Villate* and De´ cio L Eizirik Correspondence should be addressed to Medical Faculty, ULB Center for Diabetes Research and Welbio, Universite´ Libre de Bruxelles (ULB), Route de Lennik, D L Eizirik or J Juan-Mateu 808 – CP618, B-1070 Brussels, Belgium Email *(J Juan-Mateu and O Villate contributed equally to this work) [email protected] or [email protected] Abstract Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic b 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 b cells, but the intracellular signals that decide b 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 b 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 b cells, while b cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate b cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in b cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy. European Journal of Endocrinology European Journal of Endocrinology (2016) 174, R225–R238 Introduction Pre-mRNA alternative splicing (AS) is a key post-transcrip- into mature mRNA molecules, allowing single genes to tional regulatory mechanism that affects gene expression, produce multiple, structurally distinct mRNA and protein acting as a major generator of proteomic diversity. It isoforms that may have different biological properties (1). regulates the incorporation of alternative sets of exons This tightly regulated process provides cells with the Invited Author’s profile Decio L Eizirik, M.D, PhD, is Full Professor and Director of the ULB Center for Diabetes Research, Medical Faculty, Universite Libre de Bruxells (ULB), Belgium. He has published over 300 full papers and has received several prestigious awards. Prof Eizirik’s research focuses on the molecular mechanisms regulating insulitis and b cell apoptosis in type 1 diabetes and on the search for novel approaches to prevent the progressive loss of b cell mass in diabetes. www.eje-online.org Ñ 2016 European Society of Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/EJE-15-0916 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 10:47:41PM via free access Review J Juan-Mateu, O Villate and Alternative splicing and 174:5 R226 others diabetes ability to rapidly adapt their transcriptome and proteome usage of alternative exons and other components of the in response to intra and extracellular cues. Nearly 95% transcribed mRNA that are either included or excluded of human genes undergo AS, producing on average six from the final mRNA isoform (Fig. 1A). This requires the alternative isoforms per gene, thus explaining the dis- recognition of exons through the identification of a crepancy between the predicted 22 000 protein-coding complex code of cis-acting elements within the pre- genes of the human genome and the observed O200 000 mRNA molecule (Fig. 1B). The catalytic reactions that protein isoforms (2, 3). The prevalence and extent of AS occur during the splicing process are mediated by the correlates with organismal complexity, suggesting that stepwise assembly of a large and dynamic ribonucleopro- AS plays a key role for the development of complex tein (RNP) complex called the spliceosome. The spliceo- phenotypic traits during evolution (4, 5). AS regulation some is composed by five small nuclear RNP particles plays an important role in virtually all biological (snRNP), U1, U2, U4/U6 and U5, and around 200 proteins processes, including cell growth and death, development (9). The snRNP spliceosomal particles recognize the core stage, pluripotency, differentiation, circadian rhythms, splicing signals (50 splice site, branch site and polypyr- response to stimuli and disease (6, 7, 8). imidine tract-30 splice site) that are essential to carry out the splicing reaction. Core splicing signals are short and degenerate (i.e. not completely conserved) sequences that Regulation of AS: the splicing code and the coupling alone are insufficient to define intron–exon boundaries. with the transcription machinery Thus, they require the presence of additional cis-acting The splicing process involves the retention of exons and regulatory sequences to achieve fidelity in the splicing removal of introns from the pre-mRNA. This is not a rigid process. AS is accurately regulated by the interplay process, showing instead a wide variation by the different between these cis-acting regulatory elements and their A Alternative cassette exon Alternative 5′ splice site Alternative tandem cassette exons Alternative 3′ splice site European Journal of Endocrinology Mutually exclusive cassette exons Retained intron B SR proteins hnRNP U1 U2 U2AF65 35 ++– YNYURAY YYYYYYNAGG AGGURAGU Branch site 3′ splice siteESE ESS 5′ splice site ISE ISE ISS Figure 1 Regulation of alternative splicing (AS). (A) Major types of AS point, polypyrimidine tract-30 splice site) in the pre-mRNA events. Exons are represented by boxes and introns by solid molecule. Additional cis-acting regulatory sequences that lines; constitutive exons are shown in yellow while alternative regulate splice site selection in exons and introns are also exons are shown in red or blue; dashed lines represent different shown. ESE, exonic splicing enhancer; ESS, exonic splicing splicing events. (B) Schematic representation of snRNP spliceo- silencer; ISE, intronic splicing enhancer; ISS, intronic splicing somal particles bound to splicing signals (50 splice site, branch silencer. Adapted from reference (124). www.eje-online.org Downloaded from Bioscientifica.com at 09/28/2021 10:47:41PM via free access Review J Juan-Mateu, O Villate and Alternative splicing and 174:5 R227 others diabetes cognate trans-acting splicing factors, the so-called ‘splicing family of apoptotic regulators, such as Bcl2–l1, Mcl1 and code’, that either promotes or represses the recognition of BID, produce both pro- and anti-apoptotic isoforms core splicing signals (Fig. 1B). Regulatory sequences through AS, and changes in the relative ratios of these present in both exons and introns, termed splicing splice variants may lead to cancer or neurodegenerative enhancers or silencers, work as binding sites for splicing diseases by modulating cell death (23). AS can lead to factors that either enhance or repress splicing depending changes on protein localisation, enzymatic activity and on their activity and binding position (2, 10). These interaction with ligands (24). It can also modulate protein- splicing regulators are RNA-binding proteins (RBPs) of the binding properties, modifying interactions with other serine/arginine (SR)-rich proteins and heterogeneous proteins, nucleic acids or membranes. In some cases, nuclear RNPs (hnRNP) families, as well as other cell-, specific protein domains are regulated by AS, modifying stage- or tissue-specific proteins such as the NOVA, protein structure and functions. For instance, AS changes in RBFOX, CELF or MBLN families. These families establish transcriptions factors can alter the transactivation or DNA- the splicing code and determine in a combinatorial binding domains inducing negative or positive effects on fashion which splice site is selected in specific tissues (for transcription; changes on channel proteins can modify instance, NOVA1 is only expressed in brain and pancreatic their electrophysiological properties; and gene function b cells) (11, 12, 13, 14).TheregulationofASis may change from dominant negative to constitutively accomplished by the relative expression levels of the active through AS (24). By regulating the inclusion/exclu- different RBPs, determining how efficiently different splice sion of exons harbouring a stop codon or introducing a sites are used to generate specific mRNA isoforms in frameshift change, AS is often coupled with the nonsense- different cells and tissues. In addition to the splicing code, mediated mRNA decay (NMD), a quality control process defined by RBPs, regulation of AS is also influenced by that eliminates transcripts containing premature termin- other mechanisms. For instance, cis-acting RNA–RNA base ation codons, indirectly regulating mRNA expression pairing and RNA secondary structures can control the (mRNA expression results from the balance between splice site choice in some genes (15, 16, 17). Splicing mRNA
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