{"doi":"10.1172/jci.insight.179012","title":"The histone methyltransferase Mixed-lineage-leukemia-1 drives T cell phenotype via Notch signaling in diabetic tissue repair","abstract":"Immune cell-mediated inflammation is important in normal tissue regeneration but can be pathologic in diabetic wounds. Limited literature exists on the role of CD4+ T cells in normal or diabetic wound repair; however, the imbalance of CD4+ Th17/Tregs has been found to promote inflammation in other diabetic tissues. Here, using human tissue and murine transgenic models, we identified that the histone methyltransferase Mixed-lineage-leukemia-1 (MLL1) directly regulates the Th17 transcription factor RORγ via an H3K4me3 mechanism and increases expression of Notch receptors and downstream Notch signaling. Furthermore, we found that Notch receptor signaling regulates CD4+ Th cell differentiation and is critical for normal wound repair, and loss of upstream Notch pathway mediators or receptors in CD4+ T cells resulted in the loss of CD4+ Th cell differentiation in wounds. In diabetes, MLL1 and Notch-receptor signaling was upregulated in wound CD4+ Th cells, driving CD4+ T cells toward the Th17 cell phenotype. Treatment of diabetic wound CD4+ T cells with a small molecule inhibitor of MLL1 (MI-2) yielded a significant reduction in CD4+ Th17 cells and IL-17A. This is the first study to our knowledge to identify the MLL1-mediated mechanisms responsible for regulating the Th17/Treg balance in normal and diabetic wounds and to define the complex role of Notch signaling in CD4+ T cells in wounds, where increased or decreased Notch signaling both result in pathologic wound repair. Therapeutic targeting of MLL1 in diabetic CD4+ Th cells may decrease pathologic inflammation through regulation of CD4+ T cell differentiation.","journal":"JCI Insight","year":2024,"id":456470,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9492,"is_data_producer":false,"deposit_databanks":null,"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":228249,"name":"Tyler M. Bauer","orcid":"0000-0002-5430-5104","position":1,"is_corresponding":false},{"id":1281811,"name":"Kevin D Magnum","orcid":null,"position":2,"is_corresponding":false},{"id":295112,"name":"Christopher O. Audu","orcid":"0000-0002-4183-8825","position":3,"is_corresponding":false},{"id":845857,"name":"James Shadiow","orcid":"0000-0003-0293-6753","position":4,"is_corresponding":false},{"id":1221325,"name":"Emily C. Barrett","orcid":null,"position":5,"is_corresponding":false},{"id":295106,"name":"Amrita Joshi","orcid":"0000-0001-6936-7132","position":6,"is_corresponding":false},{"id":845856,"name":"Jadie Y. Moon","orcid":"0000-0001-9451-6806","position":7,"is_corresponding":false},{"id":1278353,"name":"Rachael Bogle","orcid":"0000-0003-3544-3023","position":8,"is_corresponding":false},{"id":1281812,"name":"Purba Mazumder","orcid":null,"position":9,"is_corresponding":false},{"id":295108,"name":"Sonya Wolf","orcid":"0000-0003-3626-9274","position":10,"is_corresponding":false},{"id":295113,"name":"Steven L. Kunkel","orcid":"0000-0002-5738-6341","position":11,"is_corresponding":false},{"id":12829,"name":"Jóhann E. Guðjónsson","orcid":"0000-0002-0080-0812","position":12,"is_corresponding":false},{"id":295104,"name":"Frank M. Davis","orcid":"0000-0002-5847-8993","position":13,"is_corresponding":false},{"id":250816,"name":"Katherine Gallagher","orcid":"0000-0002-8791-6980","position":14,"is_corresponding":false},{"id":295111,"name":"William J. Melvin","orcid":"0000-0002-3241-5919","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:03:32.516678Z","pmid":"39250432","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":[]}