{"doi":"10.1101/2020.07.04.187864","title":"Antagonistic epistasis of Hnf4α and FoxO1 networks through enhancer interactions in β-cell function","abstract":"Abstract Genetic and acquired abnormalities contribute to pancreatic β-cell failure in diabetes. Transcription factors Hnf4α (MODY1) and FoxO1 are respective examples of these two components, and are known to act through β-cell-specific enhancers. However, their relationship is unclear. Here we show by genome-wide interrogation of chromatin modifications that FoxO1 ablation in mature β-cells leads to increased selection of FoxO1 enhancers by Hnf4α. To model the functional significance we generated single and compound knockouts of FoxO1 and Hnf4α in β-cells. Single knockout of either gene impaired insulin secretion in mechanistically distinct fashions. Surprisingly, the defective β-cell secretory function of either single mutant in hyperglycemic clamps and isolated islets treated with various secretagogues, was completely reversed in double mutants. Gene expression analyses revealed the reversal of β-cell dysfunction with an antagonistic network regulating glycolysis, including β-cell “disallowed” genes; and that a synergistic network regulating protocadherins emerged as likely mediators of the functional restoration of insulin secretion. The findings provide evidence of antagonistic epistasis as a model of gene/environment interactions in the pathogenesis of β-cell dysfunction.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":130291,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"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":458942,"name":"Wen Du","orcid":"0000-0002-8138-774X","position":1,"is_corresponding":false},{"id":582607,"name":"Yasutaka Miyachi","orcid":"0000-0002-1487-5153","position":2,"is_corresponding":false},{"id":369839,"name":"Prasanna K. Dadi","orcid":"0000-0001-5377-5991","position":3,"is_corresponding":false},{"id":345680,"name":"David A. Jacobson","orcid":"0000-0003-1816-5375","position":4,"is_corresponding":false},{"id":104004,"name":"Domenico Accili","orcid":"0000-0002-6874-3949","position":5,"is_corresponding":false},{"id":458944,"name":"Taiyi Kuo","orcid":"0000-0001-6167-0284","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-18T23:15:53.196774Z","pmid":null,"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":[]}