title: Nova1 is a master regulator of alternative splicing in pancreatic beta cells.
abstract: Alternative splicing (AS) is a fundamental mechanism for the regulation of gene expression. It affects more than 90% of human genes but its role in the regulation of pancreatic beta cells, the producers of insulin, remains unknown. Our recently published data indicated that the 'neuron-specific' Nova1 splicing factor is expressed in pancreatic beta cells. We have presently coupled specific knockdown (KD) of Nova1 with RNA-sequencing to determine all splice variants and downstream pathways regulated by this protein in beta cells. Nova1 KD altered the splicing of nearly 5000 transcripts. Pathway analysis indicated that these genes are involved in exocytosis, apoptosis, insulin receptor signaling, splicing and transcription. In line with these findings, Nova1 silencing inhibited insulin secretion and induced apoptosis basally and after cytokine treatment in rodent and human beta cells. These observations identify a novel layer of regulation of beta cell function, namely AS controlled by key splicing regulators such as Nova1.
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium deizirik@ulb.ac.be.
authors.forename: Olatz
authors.initials: O
authors.lastname: Villate
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium.
authors.forename: Jean-Valery
authors.initials: JV
authors.lastname: Turatsinze
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium.
authors.forename: Loriana G
authors.initials: LG
authors.lastname: Mascali
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium.
authors.forename: Fabio A
authors.initials: FA
authors.lastname: Grieco
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium.
authors.forename: Tatiane C
authors.initials: TC
authors.lastname: Nogueira
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Cunha
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium.
authors.forename: Tarlliza R
authors.initials: TR
authors.lastname: Nardelli
authors.affiliation: Laboratório Nacional de Computação Científica (LNCC), Petrópolis Rio de Janeiro, 25651-076, Brazil.
authors.forename: Michael
authors.initials: M
authors.lastname: Sammeth
authors.affiliation: Lund University Diabetes Centre, Unit of Islet cell Exocytosis, Department of Clinical Sciences Malmö, Lund University, CRC 91-11, Jan Waldenströms gata 35, 205 02 Malmö, Sweden.
authors.forename: Vishal A
authors.initials: VA
authors.lastname: Salunkhe
authors.affiliation: Lund University Diabetes Centre, Unit of Islet cell Exocytosis, Department of Clinical Sciences Malmö, Lund University, CRC 91-11, Jan Waldenströms gata 35, 205 02 Malmö, Sweden.
authors.forename: Jonathan L S
authors.initials: JL
authors.lastname: Esguerra
authors.affiliation: Lund University Diabetes Centre, Unit of Islet cell Exocytosis, Department of Clinical Sciences Malmö, Lund University, CRC 91-11, Jan Waldenströms gata 35, 205 02 Malmö, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.affiliation: Department of Clinical and Experimental Medicine, Pancreatic Islet Cell Laboratory, University of Pisa, Pisa, 56126, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Marselli
authors.affiliation: Department of Clinical and Experimental Medicine, Pancreatic Islet Cell Laboratory, University of Pisa, Pisa, 56126, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium deizirik@ulb.ac.be.
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000090682:Neuro-Oncological Ventral Antigen; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1
chemical_list: D002118:Calcium; D016207:Cytokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007328:Insulin; D009419:Nerve Tissue Proteins; D000090682:Neuro-Oncological Ventral Antigen; D016601:RNA-Binding Proteins; D011972:Receptor, Insulin; C499515:FOXO3 protein, rat; C000594513:NOVA1 protein, human; C000594514:Nova1 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1