A role for alternative splicing in circadian control of exocytosis and glucose homeostasis.
Genes Dev
; 34(15-16): 1089-1105, 2020 08 01.
Article
in En
| MEDLINE
| ID: mdl-32616519
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 ß cells that are perturbed in Clock-/- and Bmal1-/- ß-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 ß 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 ß-cell function across the sleep/wake cycle.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Alternative Splicing
/
Exocytosis
/
Circadian Clocks
/
Insulin Secretion
/
Glucose
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Genes Dev
Journal subject:
BIOLOGIA MOLECULAR
Year:
2020
Type:
Article
Affiliation country:
United States