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

Biliana Marcheva, Mark Perelis, Benjamin J. Weidemann, Akihiko Taguchi, Haopeng Lin, Chiaki Omura, Yumiko Kobayashi, Marsha V. Newman, Eugene J. Wyatt, Elizabeth M. McNally, Jocelyn E. Manning Fox, Heekyung Hong, Archana Shankar, Emily C. Wheeler, Kathryn Moynihan Ramsey, Patrick E. MacDonald, Gene W. Yeo, Joseph Bass*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 Clock-/- and Bmal1-/- 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 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 β-cell function across the sleep/wake cycle.

Original languageEnglish (US)
Pages (from-to)1089-1105
Number of pages17
JournalGenes and Development
Volume34
Issue number15-16
DOIs
StatePublished - 2020

Keywords

  • Alternative splicing
  • CASK
  • Circadian clock
  • Exocytosis
  • Insulin secretion
  • MADD
  • RNA sequencing
  • SNAP25]
  • THRAP3
  • Transcriptomics

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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