Pancreatic microexons regulate islet function and glucose homeostasis

Pancreatic islets control glucose homeostasis by the balanced secretion of insulin and other hormones, and their abnormal function causes diabetes or hypoglycaemia. Here we uncover a conserved programme of alternative microexons included in mRNAs of islet cells, particularly in genes involved in vesicle transport and exocytosis. Islet microexons (IsletMICs) are regulated by the RNA binding protein SRRM3 and represent a subset of the larger neural programme that are particularly sensitive to SRRM3 levels. Both SRRM3 and IsletMICs are induced by elevated glucose levels, and depletion of SRRM3 in human and rat beta cell lines and mouse islets, or repression of particular IsletMICs using antisense oligonucleotides, leads to inappropriate insulin secretion. Consistently, mice harbouring mutations in Srrm3 display defects in islet cell identity and function, leading to hyperinsulinaemic hypoglycaemia. Importantly, human genetic variants that influence SRRM3 expression and IsletMIC inclusion in islets are associated with fasting glucose variation and type 2 diabetes risk. Taken together, our data identify a conserved microexon programme that regulates glucose homeostasis.We thank B. Banfi (University of Iowa) for kindly sharing the Srrm3 gene-trapped mouse line with us; M. Ángel Maestro for excellent technical advice on multiple protocols related to the study of Srrm3 mutant mice; J. Permanyer and C. Rodriguez for help with mouse genotyping; D. Balboa, I. Miguel-Escalada and E. Bernardo, as well as members of the M.I. and J.V. groups for constant scientific discussion; A. Gohr for assistance on bioinformatic analyses; S. Taylor (University of Manchester) for kindly sharing the HeLa Flp-In T-Rex cell line with us; and CRG Genomics and Advanced Light Microscopy Units for the RNA-seq and microscopy services. The research has been funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (ERC-StG-LS2-637591 and ERCCoG-LS2-101002275 to M.I., ERC-AdG-LS2-670146 to J.V., and ERC-AdG-LS4-789055 to J.F.), EU Horizon 2020 TDSystems (667191) to J.F., la Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR20/52400008 to M.I., an EFSD award supported by EFSD/Lilly European Diabetes Research Programme, the Spanish Ministry of Science and Innovation (BFU-2017-89308-P to J.V., BFU-2017-89201-P to M.I. and RTI2018-095666-B-I00 to J.F.) and the ‘Centro de Excelencia Severo Ochoa’ (CEX2020-001049). G.A. was supported by the Marie Skłodowska-Curie project ZENCODE-ITN (No. 643062). S.B.-G. was supported by a Juan de la Cierva postdoctoral fellowship (MINECO; FJCI-2017-32090). J.J.-M. was supported by the Beatriu de Pinós Programme and the Ministry of Research and Universities of the Government of Catalonia, and a Marie Skłodowska-Curie Individual Fellowship from the European Union’s Horizon 2020 research and innovation programme (MSCA-IF-2019-841758; http://ec.europa.eu/)