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><sup>-/-</sup> and <i>Bmal1</i><sup>-/-</sup> 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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Linked Datasets (1)
A role for alternative splicing in circadian control of insulin secretion and glucose homeostasis
Mus musculus23 data files
| File | Type | Size |
|---|---|---|
| BKO_RNA_1_R1.fastq | RNA-Seq | 1.4 GB |
| BKO_RNA_2_R1.fastq | RNA-Seq | 1.8 GB |
| BKO_RNA_3_R1.fastq | RNA-Seq | 1.2 GB |
| BKO_THRAP3_ChIPseq_Input.fq.gz | ChIP-Seq | 476.9 MB |
| BKO_THRAP3_ChIPseq_rep1.fq.gz | ChIP-Seq | 580.2 MB |
| BKO_THRAP3_ChIPseq_rep2.fq.gz | ChIP-Seq | 650.8 MB |
| BKO_THRAP3_eCLIP_input1.fastq.gz | OTHER | 1.3 GB |
| BKO_THRAP3_eCLIP_input2.fastq.gz | OTHER | 471.0 MB |
| BKO_THRAP3_eCLIP_IP1.fastq.gz | OTHER | 907.5 MB |
| BKO_THRAP3_eCLIP_IP2.fastq.gz | OTHER | 685.2 MB |
| CKO_RNA_1_R1.fastq | RNA-Seq | 1.3 GB |
| CKO_RNA_2_R1.fastq | RNA-Seq | 1.1 GB |
| CKO_RNA_3_R1.fastq | RNA-Seq | 1.1 GB |
| WT_RNA_1_R1.fastq | RNA-Seq | 1.4 GB |
| WT_RNA_2_R1.fastq | RNA-Seq | 1.3 GB |
| WT_RNA_3_R1.fastq | RNA-Seq | 1.1 GB |
| WT_THRAP3_ChIPseq_Input.fq.gz | ChIP-Seq | 513.4 MB |
| WT_THRAP3_ChIPseq_rep1.fq.gz | ChIP-Seq | 567.5 MB |
| WT_THRAP3_ChIPseq_rep2.fq.gz | ChIP-Seq | 578.3 MB |
| WT_THRAP3_eCLIP_input1.fastq.gz | OTHER | 1.5 GB |
| WT_THRAP3_eCLIP_input2.fastq.gz | OTHER | 1.1 GB |
| WT_THRAP3_eCLIP_IP1.fastq.gz | OTHER | 1.7 GB |
| WT_THRAP3_eCLIP_IP2.fastq.gz | OTHER | 930.9 MB |
Potentially Related Datasets (3)
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
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