{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:18:48Z","timestamp":1785406728225,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,20]]},"group-title":"Developmental Biology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01HD115718"],"award-info":[{"award-number":["R01HD115718"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R03HD112717-01"],"award-info":[{"award-number":["1R03HD112717-01"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001680","name":"Charles H. Hood Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001680","id-type":"DOI","asserted-by":"crossref"}]},{"award":["CA-1052191"],"award-info":[{"award-number":["CA-1052191"]}],"id":[{"id":"https:\/\/ror.org\/01p3rh655","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  KMT2D, the histone methyltransferase and core component of the COMPASS\/MLL4 complex, has been implicated in developmental diseases such as Kabuki Syndrome, interstitial lung disease, and congenital diaphragmatic hernia, with clear links to pediatric pulmonary disorders. Despite this, the mechanism by which KMT2D governs lung development remains unclear. Knock-in mouse models rendering, KMT2D catalytically deactivated (KMT2D\n                  <jats:sup>KI<\/jats:sup>\n                  ) and reducing H3K4 methylation, have demonstrated potential in defining KMT2D\u2019s role in pulmonary development. Our examination of the lungs of KMT2D\n                  <jats:sup>KI<\/jats:sup>\n                  mice revealed increased cellular density and impaired sacculation indicated by reduced airspace chord length, thickening of intersaccular septa, and abnormal alveolar cell differentiation. KMT2D\n                  <jats:sup>KI<\/jats:sup>\n                  mice revealed narrowed Sox2+ conducting airways and epithelial differentiation defects characterized by reduced Cc10+ club cells. Accompanying the alveolar and airway hypoplasia, blood vessel luminal area was reduced. Conversely, KMT2D\n                  <jats:sup>KI<\/jats:sup>\n                  lungs had a significantly higher proportion of proliferating cells accompanied by a dramatic expansion in Pdgfr\u03b1+ mesenchymal progenitor cells. Our findings therefore suggest that KMT2D-mediated H3K4 methylation is vital to normal lung development, and its impairment results in widespread pulmonary hypoplasia and potentially pulmonary hypertension.\n                <\/jats:p>","DOI":"10.64898\/2026.03.18.712755","type":"posted-content","created":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T04:05:17Z","timestamp":1774065917000},"source":"Crossref","is-referenced-by-count":0,"title":["Histone methylation activity of KMT2D is required for proliferative control of the developing lung"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7170-9568","authenticated-orcid":false,"given":"Aalekh S.","family":"Mehta","sequence":"first","affiliation":[{"name":"Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8250-6157","authenticated-orcid":false,"given":"Guojia","family":"Xie","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5614-1257","authenticated-orcid":false,"given":"Frances A.","family":"High","sequence":"additional","affiliation":[{"name":"Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5502-4497","authenticated-orcid":false,"given":"Patricia K.","family":"Donahoe","sequence":"additional","affiliation":[{"name":"Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Harvard Stem Cell Institute, Cambridge, MA 02138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0618-1132","authenticated-orcid":false,"given":"Samuel P.","family":"Rowbotham","sequence":"additional","affiliation":[{"name":"Pediatric Surgical Research Laboratories, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02115, USA"},{"name":"Harvard Stem Cell Institute, Cambridge, MA 02138, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032407151008000_2026.03.18.712755v1.1","first-page":"299","article-title":"Histone variants and chromatin structure, update of advances","volume":"21","year":"2022","journal-title":"Comput. Struct. Biotechnol. J"},{"key":"2026032407151008000_2026.03.18.712755v1.2","doi-asserted-by":"crossref","first-page":"e292","DOI":"10.1002\/mco2.292","article-title":"Post-translational modifications of histones: mechanisms, biological functions, and therapeutic targets","volume":"4","year":"2023","journal-title":"MedComm"},{"key":"2026032407151008000_2026.03.18.712755v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-019-0298-7"},{"key":"2026032407151008000_2026.03.18.712755v1.4","doi-asserted-by":"crossref","unstructured":"Bozdemir, N. et al. A comprehensive review of histone modifications during mammalian oogenesis and early embryo development. Histochem. Cell Biol. 163, 70 (2025).","DOI":"10.1007\/s00418-025-02398-x"},{"key":"2026032407151008000_2026.03.18.712755v1.5","doi-asserted-by":"publisher","DOI":"10.2217\/epi.14.60"},{"key":"2026032407151008000_2026.03.18.712755v1.6","doi-asserted-by":"publisher","DOI":"10.2217\/epi.15.1"},{"key":"2026032407151008000_2026.03.18.712755v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2024.06.001"},{"key":"2026032407151008000_2026.03.18.712755v1.8","doi-asserted-by":"crossref","unstructured":"Hsu, C. L. et al. H3K4 methylation in aging and metabolism. Epigenomes 5, 14 (2021).","DOI":"10.3390\/epigenomes5020014"},{"key":"2026032407151008000_2026.03.18.712755v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-020-0278-0"},{"key":"2026032407151008000_2026.03.18.712755v1.10","doi-asserted-by":"crossref","unstructured":"Barral, A. & D\u00e9jardin, J . The chromatin signatures of enhancers and their dynamic regulation. Nucleus 14, 2160551 (2023).","DOI":"10.1080\/19491034.2022.2160551"},{"key":"2026032407151008000_2026.03.18.712755v1.11","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.01503"},{"key":"2026032407151008000_2026.03.18.712755v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23026"},{"key":"2026032407151008000_2026.03.18.712755v1.13","doi-asserted-by":"crossref","unstructured":"Deng, X. et al. Pulmonary hypertension\u2014a novel phenotypic hypothesis of Kabuki syndrome: a case report and literature review. BMC Pediatr. 23, 429 (2023).","DOI":"10.1186\/s12887-023-04273-x"},{"key":"2026032407151008000_2026.03.18.712755v1.14","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1002\/ajmg.a.61518","article-title":"Phenotypic expansion of KMT2D-related disorder: beyond Kabuki syndrome","volume":"182","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"2026032407151008000_2026.03.18.712755v1.15","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/RTI.0000000000000350","article-title":"Pulmonary manifestations of common variable immunodeficiency","volume":"33","year":"2018","journal-title":"J. Thorac. Imaging"},{"key":"2026032407151008000_2026.03.18.712755v1.16","doi-asserted-by":"crossref","unstructured":"Ba, X. et al. Case report of Kabuki syndrome in a newborn caused by KMT2D gene mutation. Front. Pediatr. 12, 1455609 (2024).","DOI":"10.3389\/fped.2024.1455609"},{"key":"2026032407151008000_2026.03.18.712755v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.08.011"},{"key":"2026032407151008000_2026.03.18.712755v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.08.024"},{"key":"2026032407151008000_2026.03.18.712755v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.005"},{"key":"2026032407151008000_2026.03.18.712755v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.11.015"},{"key":"2026032407151008000_2026.03.18.712755v1.21","doi-asserted-by":"crossref","first-page":"3338","DOI":"10.21037\/jtd-24-134","article-title":"Somatic KMT2D loss-of-function mutations in lung squamous cell carcinoma: a single-center cohort study","volume":"16","year":"2024","journal-title":"J. Thorac. Dis"},{"key":"2026032407151008000_2026.03.18.712755v1.22","doi-asserted-by":"crossref","first-page":"778","DOI":"10.4143\/crt.2022.1042","article-title":"MLL4 regulates the progression of non-small-cell lung cancer by regulating the PI3K\/AKT\/SOX2 axis","volume":"55","year":"2023","journal-title":"Cancer Res. Treat"},{"key":"2026032407151008000_2026.03.18.712755v1.23","doi-asserted-by":"crossref","unstructured":"Lavery, W. J. et al. KMT2C\/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies. Clin. Epigenetics 12, 10 (2020).","DOI":"10.1186\/s13148-019-0802-2"},{"key":"2026032407151008000_2026.03.18.712755v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00724-8"},{"key":"2026032407151008000_2026.03.18.712755v1.25","doi-asserted-by":"publisher","DOI":"10.1101\/gad.339762.120"},{"key":"2026032407151008000_2026.03.18.712755v1.26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.14.2741"},{"key":"2026032407151008000_2026.03.18.712755v1.27","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24125"},{"key":"2026032407151008000_2026.03.18.712755v1.28","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1002\/bdr2.2253","article-title":"SETting up the genome: KMT2D and KDM6A genomic function in the Kabuki syndrome craniofacial developmental disorder","volume":"115","year":"2023","journal-title":"Birth Defects Res"},{"key":"2026032407151008000_2026.03.18.712755v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01356-4"},{"key":"2026032407151008000_2026.03.18.712755v1.30","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2020-107317"},{"key":"2026032407151008000_2026.03.18.712755v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/J.DEVCEL.2023.10.011"},{"key":"2026032407151008000_2026.03.18.712755v1.32","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad7969"},{"key":"2026032407151008000_2026.03.18.712755v1.33","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.160.4.9810071"},{"key":"2026032407151008000_2026.03.18.712755v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2014.12.007"},{"key":"2026032407151008000_2026.03.18.712755v1.35","doi-asserted-by":"publisher","DOI":"10.1378\/chest.06-2194"},{"key":"2026032407151008000_2026.03.18.712755v1.36","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0346OC"},{"key":"2026032407151008000_2026.03.18.712755v1.37","unstructured":"Goldin, J. & Cascella, M. Diffusing capacity of the lungs for carbon monoxide. In StatPearls (StatPearls Publishing, 2025)."},{"key":"2026032407151008000_2026.03.18.712755v1.38","doi-asserted-by":"crossref","unstructured":"Cappuccio, G. et al. Bronchial isomerism in a Kabuki syndrome patient with a novel mutation in MLL2 gene. BMC Med. Genet. 15, 15 (2014).","DOI":"10.1186\/1471-2350-15-15"},{"key":"2026032407151008000_2026.03.18.712755v1.39","doi-asserted-by":"crossref","unstructured":"Leonardi, L. et al. Immune dysregulation in Kabuki syndrome: a case report of Evans syndrome and hypogammaglobulinemia. Front. Pediatr. 11, 1087002 (2023).","DOI":"10.3389\/fped.2023.1087002"},{"key":"2026032407151008000_2026.03.18.712755v1.40","doi-asserted-by":"crossref","first-page":"68","DOI":"10.21037\/tlcr.2017.01.02","article-title":"Pulmonary ground-glass opacity: computed tomography features, histopathology and molecular pathology","volume":"6","year":"2017","journal-title":"Transl. Lung Cancer Res"},{"key":"2026032407151008000_2026.03.18.712755v1.41","doi-asserted-by":"crossref","unstructured":"Glickman, S. et al. Kabuki syndrome presenting with severe anemia secondary to pulmonary hemosiderosis. Ann. Allergy Asthma Immunol. 133, S167 (2024).","DOI":"10.1016\/j.anai.2024.08.657"},{"key":"2026032407151008000_2026.03.18.712755v1.42","doi-asserted-by":"crossref","unstructured":"Ota, C. et al. Dynamic expression of HOPX in alveolar epithelial cells reflects injury and repair during the progression of pulmonary fibrosis. Sci. Rep. 8, 12983 (2018).","DOI":"10.1038\/s41598-018-31214-x"},{"key":"2026032407151008000_2026.03.18.712755v1.43","doi-asserted-by":"crossref","unstructured":"Hng, C. H. et al. HOPX regulates bone marrow-derived mesenchymal stromal cell fate determination via suppression of adipogenic gene pathways. Sci. Rep. 10, 11345 (2020).","DOI":"10.1038\/s41598-020-68261-2"},{"key":"2026032407151008000_2026.03.18.712755v1.44","doi-asserted-by":"crossref","unstructured":"Ashokkumar, D. et al. MLL4 is required after implantation, whereas MLL3 becomes essential during late gestation. Development 147, dev186999 (2020).","DOI":"10.1242\/dev.186999"},{"key":"2026032407151008000_2026.03.18.712755v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2018.03.005"},{"key":"2026032407151008000_2026.03.18.712755v1.46","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00192.2022"},{"key":"2026032407151008000_2026.03.18.712755v1.47","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.160.3.9803113"},{"key":"2026032407151008000_2026.03.18.712755v1.48","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1164\/rccm.202205-0953OC","article-title":"A tracheal aspirate-derived airway basal cell model reveals a proinflammatory epithelial defect in congenital diaphragmatic hernia","volume":"207","year":"2023","journal-title":"Am. J. Respir. Crit. Care Med"},{"key":"2026032407151008000_2026.03.18.712755v1.49","doi-asserted-by":"crossref","unstructured":"Comel, M. et al. Abnormal immune profile in individuals with Kabuki syndrome. J. Clin. Immunol. 45, 7 (2025).","DOI":"10.1007\/s10875-024-01796-5"},{"key":"2026032407151008000_2026.03.18.712755v1.50","doi-asserted-by":"crossref","unstructured":"McNulty, W. & Usmani, O. S . Techniques of assessing small airways dysfunction. Eur. Clin. Respir. J. 1, 25898 (2014).","DOI":"10.3402\/ecrj.v1.25898"},{"key":"2026032407151008000_2026.03.18.712755v1.51","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1097\/CM9.0000000000001724","article-title":"Computed tomography-identified phenotypes of small airway obstructions in chronic obstructive pulmonary disease","volume":"134","year":"2021","journal-title":"Chin. Med. J"},{"key":"2026032407151008000_2026.03.18.712755v1.52","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/1096-8628(20000911)94:2<170::AID-AJMG10>3.0.CO;2-2","article-title":"Unexpected life-threatening complications in Kabuki syndrome","volume":"94","year":"2000","journal-title":"Am. J. Med. Genet"},{"key":"2026032407151008000_2026.03.18.712755v1.53","doi-asserted-by":"crossref","first-page":"e1011608","DOI":"10.1371\/journal.pgen.1011608","article-title":"Epigenome and transcriptome changes in KMT2D-related Kabuki syndrome type 1 iPSCs, neuronal progenitors and cortical neurons","volume":"21","year":"2025","journal-title":"PLoS Genet"},{"key":"2026032407151008000_2026.03.18.712755v1.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-022-00877-0"},{"key":"2026032407151008000_2026.03.18.712755v1.55","first-page":"66","article-title":"Premature monozygotic twins with congenital diaphragmatic hernia: a case report","volume":"25","year":"2025","journal-title":"Sudan J. Paediatr"},{"key":"2026032407151008000_2026.03.18.712755v1.56","doi-asserted-by":"crossref","first-page":"e2413299","DOI":"10.1002\/advs.202413299","article-title":"Adrenal high-expressional CYP27A1 mediates bile acid increase and functional impairment in adult male offspring by prenatal dexamethasone exposure","volume":"12","year":"2025","journal-title":"Adv. Sci"},{"key":"2026032407151008000_2026.03.18.712755v1.57","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.bbi.2017.09.004","article-title":"Chromatin organization as an indicator of glucocorticoid induced natural killer cell dysfunction","volume":"67","year":"2018","journal-title":"Brain Behav. Immun"},{"key":"2026032407151008000_2026.03.18.712755v1.58","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1165\/rcmb.2023-0138OC","article-title":"Overactivated epithelial NF-\u03baB disrupts lung development in congenital diaphragmatic hernia","volume":"69","year":"2023","journal-title":"Am. J. Respir. Cell Mol. Biol"},{"key":"2026032407151008000_2026.03.18.712755v1.59","doi-asserted-by":"publisher","DOI":"10.1242\/dev.116947"},{"key":"2026032407151008000_2026.03.18.712755v1.60","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.steroids.2013.12.001","article-title":"Glucocorticoid dexamethasone regulates the differentiation of mouse conducting airway epithelial progenitor cells","volume":"80","year":"2014","journal-title":"Steroids"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.18.712755","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T14:15:28Z","timestamp":1774361728000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.18.712755"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,20]]},"references-count":60,"URL":"https:\/\/doi.org\/10.64898\/2026.03.18.712755","relation":{},"subject":[],"published":{"date-parts":[[2026,3,20]]},"subtype":"preprint"}}