{"doi":"10.1101/gad.338178.120","title":"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 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.","journal":"Genes & Development","year":2020,"id":119010,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":31,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":552670,"name":"Mark Perelis","orcid":"0000-0001-5435-2552","position":1,"is_corresponding":false},{"id":552671,"name":"Benjamin J. Weidemann","orcid":"0000-0002-3747-2744","position":2,"is_corresponding":false},{"id":552672,"name":"Akihiko Taguchi","orcid":"0000-0001-8544-5698","position":3,"is_corresponding":false},{"id":553354,"name":"Haopeng Lin","orcid":null,"position":4,"is_corresponding":false},{"id":552673,"name":"Chiaki Omura","orcid":"0000-0003-4810-4290","position":5,"is_corresponding":false},{"id":318480,"name":"Yumiko Kobayashi","orcid":"0000-0002-4578-6743","position":6,"is_corresponding":false},{"id":553355,"name":"Marsha Newman","orcid":null,"position":7,"is_corresponding":false},{"id":243934,"name":"Eugene Wyatt","orcid":null,"position":8,"is_corresponding":false},{"id":297686,"name":"Elizabeth M. McNally","orcid":"0000-0002-1221-719X","position":9,"is_corresponding":false},{"id":255373,"name":"Jocelyn E. Manning Fox","orcid":"0000-0002-4157-2094","position":10,"is_corresponding":false},{"id":507650,"name":"Hee‐Kyung Hong","orcid":null,"position":11,"is_corresponding":false},{"id":264301,"name":"Archana Shankar","orcid":"0000-0003-3499-4309","position":12,"is_corresponding":false},{"id":284761,"name":"Emily C. Wheeler","orcid":"0000-0003-0260-8530","position":13,"is_corresponding":false},{"id":552674,"name":"Kathryn Moynihan Ramsey","orcid":"0000-0002-0691-7835","position":14,"is_corresponding":false},{"id":7384,"name":"Patrick E. MacDonald","orcid":"0000-0002-5439-6288","position":15,"is_corresponding":false},{"id":43290,"name":"G Yeo","orcid":null,"position":16,"is_corresponding":false},{"id":506968,"name":"Joseph Bass","orcid":"0000-0002-1602-8601","position":17,"is_corresponding":false},{"id":552669,"name":"Biliana Marcheva","orcid":"0000-0001-8697-2625","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-18T23:14:03.409507Z","pmid":"32616519","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}