{"doi":"10.1101/gad.352193.124","title":"NKX2.2 and KLF4 cooperate to regulate α-cell identity","abstract":"Transcription factors (TFs) are indispensable for maintaining cell identity through regulating cell-specific gene expression. Distinct cell identities derived from a common progenitor are frequently perpetuated by shared TFs, yet the mechanisms that enable these TFs to regulate cell-specific targets are poorly characterized. We report that the TF NKX2.2 is critical for the identity of pancreatic islet α cells by directly activating α-cell genes and repressing alternate islet cell fate genes. When compared with the known role of NKX2.2 in islet β cells, we demonstrate that NKX2.2 regulates α-cell genes, facilitated in part by α-cell-specific DNA binding at gene promoters. Furthermore, we have identified the reprogramming factor KLF4 as having enriched expression in α cells, where it co-occupies NKX2.2-bound α-cell promoters, is necessary for NKX2.2 promoter occupancy in α cells, and coregulates many NKX2.2 α-cell transcriptional targets. Overexpression of Klf4 in β cells is sufficient to manipulate chromatin accessibility, increase binding of NKX2.2 at α-cell-specific promoter sites, and alter expression of NKX2.2-regulated cell-specific targets. This study identifies KLF4 as a novel α-cell factor that cooperates with NKX2.2 to regulate α-cell identity.","journal":"Genes & Development","year":2024,"id":486497,"datarank":0.273850557252483,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.03243487038736791,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.03243487038736791,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":3,"citers_with_citation_signal":2,"citers_with_endowment":2,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE273739","GSE273740","GSE273741","GSE273742","GSE273743","GSE273744","GSE273745"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1330741,"name":"McKenna R. Casey","orcid":null,"position":1,"is_corresponding":false},{"id":282722,"name":"Kristen L. Wells","orcid":"0000-0002-7466-8164","position":2,"is_corresponding":false},{"id":1330742,"name":"Tsung-Yun Liu","orcid":null,"position":3,"is_corresponding":false},{"id":1330743,"name":"Madeline Van Orman","orcid":null,"position":4,"is_corresponding":false},{"id":449848,"name":"Lori Sussel","orcid":"0000-0003-4672-7304","position":5,"is_corresponding":false},{"id":473689,"name":"Elliott P. Brooks","orcid":"0000-0001-6981-1205","position":0,"is_corresponding":true}],"reference_count":85,"raw_metadata":null,"created_at":"2026-07-19T02:08:01.404471Z","pmid":"39797760","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":[]}