RT Journal Article
SR Electronic
T1 Control of pancreatic islet function and glucose homeostasis by a novel microexon program misregulated in type 2 diabetes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.02.486809
DO 10.1101/2022.04.02.486809
A1 Jonàs Juan-Mateu
A1 Simon Bajew
A1 Marta Miret
A1 Luis P. Íñiguez
A1 Amaya López
A1 Sophie Bonnal
A1 Goutham Atla
A1 Sílvia Bonàs-Guarch
A1 Jorge Ferrer
A1 Juan Valcárcel
A1 Manuel Irimia
YR 2022
UL http://biorxiv.org/content/early/2022/04/02/2022.04.02.486809.abstract
AB Pancreatic islets control glucose homeostasis by the balanced secretion of insulin and other hormones, and its abnormal function causes diabetes or hypoglycemia. Here, we uncover a conserved program 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 program that are particularly sensitive to the levels of this regulator. Both SRRM3 and IsletMICs are induced by elevated glucose levels, and depletion of SRRM3 in beta cell lines and mouse islets, or repression of particular IsletMICs using antisense oligonucleotides, leads to inappropriate insulin secretion. Consistently, SRRM3 mutant mice display defects in islet cell identity and function, leading to hyperinsulinemic hypoglycemia. Importantly, human genetic variants that influence SRRM3 expression and IsletMIC inclusion in islets are associated with fasting glucose variation and type 2 diabetes risk.Competing Interest StatementThe authors have declared no competing interest.