{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T17:40:17Z","timestamp":1793814017413,"version":"4.6.1"},"reference-count":60,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T00:00:00Z","timestamp":1728432000000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-HL137919,R01-DK124290,R01- AR079863 01,R01- HL156274-01A1,R01- DK 127531 01 A1,F32-AWD023945,F32 - HL15250801"],"award-info":[{"award-number":["R01-HL137919,R01-DK124290,R01- AR079863 01,R01- HL156274-01A1,R01- DK 127531 01 A1,F32-AWD023945,F32 - HL15250801"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,8]]},"abstract":"<jats:p>\n                    Immune cell\u2013mediated inflammation is important in normal tissue regeneration but can be pathologic in diabetic wounds. Limited literature exists on the role of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells in normal or diabetic wound repair; however, the imbalance of CD4\n                    <jats:sup>+<\/jats:sup>\n                    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 ROR\u03b3 via an H3K4me3 mechanism and increases expression of Notch receptors and downstream Notch signaling. Furthermore, we found that Notch receptor signaling regulates CD4\n                    <jats:sup>+<\/jats:sup>\n                    Th cell differentiation and is critical for normal wound repair, and loss of upstream Notch pathway mediators or receptors in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells resulted in the loss of CD4\n                    <jats:sup>+<\/jats:sup>\n                    Th cell differentiation in wounds. In diabetes, MLL1 and Notch-receptor signaling was upregulated in wound CD4\n                    <jats:sup>+<\/jats:sup>\n                    Th cells, driving CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells toward the Th17 cell phenotype. Treatment of diabetic wound CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells with a small molecule inhibitor of MLL1 (MI-2) yielded a significant reduction in CD4\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    T cells in wounds, where increased or decreased Notch signaling both result in pathologic wound repair. Therapeutic targeting of MLL1 in diabetic CD4\n                    <jats:sup>+<\/jats:sup>\n                    Th cells may decrease pathologic inflammation through regulation of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell differentiation.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.179012","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T13:04:36Z","timestamp":1725887076000},"source":"Crossref","is-referenced-by-count":10,"title":["The histone methyltransferase Mixed-lineage-leukemia-1 drives T cell phenotype via Notch signaling in diabetic tissue repair"],"prefix":"10.1172","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3241-5919","authenticated-orcid":true,"given":"William J.","family":"Melvin","sequence":"first","affiliation":[{"name":"Section of Vascular Surgery, Department of Surgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler 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C.","family":"Barrett","sequence":"additional","affiliation":[{"name":"Section of Vascular Surgery, Department of Surgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita D.","family":"Joshi","sequence":"additional","affiliation":[{"name":"Section of Vascular Surgery, Department of Surgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadie Y.","family":"Moon","sequence":"additional","affiliation":[{"name":"Section of Vascular Surgery, Department of Surgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Bogle","sequence":"additional","affiliation":[{"name":"Department of Dermatology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purba","family":"Mazumder","sequence":"additional","affiliation":[{"name":"Section of Vascular Surgery, Department of Surgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonya 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