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Nucleic Acids Res. 2014 Oct;42(18):11818-30. doi: 10.1093/nar/gku861. Epub 2014 Sep 23.

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

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ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels (ULB) B-1070, Belgium.
Laboratório Nacional de Computação Científica (LNCC), Petrópolis Rio de Janeiro, 25651-076, Brazil.
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.
Department of Clinical and Experimental Medicine, Pancreatic Islet Cell Laboratory, University of Pisa, Pisa, 56126, Italy.


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.

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