A role for alternative splicing in circadian control of exocytosis and glucose homeostasis.

Abstract

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 β cells that are perturbed in <i>Clock</i>^-/- and <i>Bmal1</i>^-/- β-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 β cells, including transcripts encoding <i>Cask</i> (<i>calcium/calmodulin-dependent serine protein kinase</i>) and <i>Madd</i> (<i>MAP kinase-activating death domain</i>). Depletion of THRAP3 restores expression of the long isoforms of <i>Cask</i> and <i>Madd</i>, 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 β-cell function across the sleep/wake cycle.

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