{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T00:14:57Z","timestamp":1793146497804,"version":"4.5.0"},"reference-count":61,"publisher":"American Society for Clinical Investigation","issue":"20","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,17]]},"abstract":"<jats:p>\n                    Chromatin modifiers act to coordinate gene expression changes critical to neuronal differentiation from neural stem\/progenitor cells (NSPCs). Lysine-specific methyltransferase 2D (\n                    <jats:italic>KMT2D<\/jats:italic>\n                    ) encodes a histone methyltransferase that promotes transcriptional activation and is frequently mutated in cancers and in the majority (&gt;70%) of patients diagnosed with the congenital, multisystem intellectual disability disorder Kabuki syndrome 1 (KS1). Critical roles for KMT2D are established in various non-neural tissues, but the effects of KMT2D loss in brain cell development have not been described. We conducted parallel studies of proliferation, differentiation, transcription, and chromatin profiling in KMT2D-deficient human and mouse models to define KMT2D-regulated functions in neurodevelopmental contexts, including adult-born hippocampal NSPCs in vivo and in vitro. We report cell-autonomous defects in proliferation, cell cycle, and survival, accompanied by early NSPC maturation in several KMT2D-deficient model systems. Transcriptional suppression in KMT2D-deficient cells indicated strong perturbation of hypoxia-responsive metabolism pathways. Functional experiments confirmed abnormalities of cellular hypoxia responses in KMT2D-deficient neural cells and accelerated NSPC maturation in vivo. Together, our findings support a model in which loss of KMT2D function suppresses expression of oxygen-responsive gene programs important to neural progenitor maintenance, resulting in precocious neuronal differentiation in a mouse model of KS1.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.129375","type":"journal-article","created":{"date-parts":[[2019,8,29]],"date-time":"2019-08-29T14:13:07Z","timestamp":1567087987000},"source":"Crossref","is-referenced-by-count":64,"title":["Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome"],"prefix":"10.1172","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9142-8525","authenticated-orcid":true,"given":"Giovanni A.","family":"Carosso","sequence":"first","affiliation":[{"name":"Predoctoral Training Program in Human Genetics,"},{"name":"McKusick-Nathans Institute of Genetic Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandros","family":"Boukas","sequence":"additional","affiliation":[{"name":"Predoctoral Training Program in Human Genetics,"},{"name":"McKusick-Nathans Institute of Genetic Medicine,"},{"name":"Department of Biostatistics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3302-4426","authenticated-orcid":true,"given":"Jonathan J.","family":"Augustin","sequence":"additional","affiliation":[{"name":"McKusick-Nathans Institute of Genetic Medicine,"},{"name":"Predoctoral Training Program in Biochemistry, Cellular, and Molecular Biology,"},{"name":"Solomon H. 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