| First Author | Marcheva B | Year | 2020 |
| Journal | Genes Dev | Volume | 34 |
| Issue | 15-16 | Pages | 1089-1105 |
| PubMed ID | 32616519 | Mgi Jnum | J:302537 |
| Mgi Id | MGI:6507900 | Doi | 10.1101/gad.338178.120 |
| Citation | Marcheva B, et al. (2020) A role for alternative splicing in circadian control of exocytosis and glucose homeostasis. Genes Dev 34(15-16):1089-1105 |
| abstractText | The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic beta cells that are perturbed in Clock (-/-) and Bmal1 (-/-) beta-cell lines. We show that the RNA-binding protein THRAP3 (thyroid hormone receptor-associated protein 3) regulates circadian clock-dependent AS by binding to exons at coding sequences flanking exons that are more frequently skipped in clock mutant beta cells, including transcripts encoding Cask (calcium/calmodulin-dependent serine protein kinase) and Madd (MAP kinase-activating death domain). Depletion of THRAP3 restores expression of the long isoforms of Cask and Madd, and mimicking exon skipping in these transcripts through antisense oligonucleotide delivery in wild-type islets reduces glucose-stimulated insulin secretion. Finally, we identify shared networks of alternatively spliced exocytic genes from islets of rodent models of diet-induced obesity that significantly overlap with clock mutants. Our results establish a role for pre-mRNA alternative splicing in beta-cell function across the sleep/wake cycle. |
