PT - JOURNAL ARTICLE AU - Giovanni A. Carosso AU - Leandros Boukas AU - Jonathan J. Augustin AU - Ha Nam Nguyen AU - Briana L. Winer AU - Gabrielle H. Cannon AU - Johanna D. Robertson AU - Li Zhang AU - Kasper D. Hansen AU - Loyal A. Goff AU - Hans T. Bjornsson TI - Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome AID - 10.1101/484410 DP - 2019 Jan 01 TA - bioRxiv PG - 484410 4099 - http://biorxiv.org/content/early/2019/08/05/484410.short 4100 - http://biorxiv.org/content/early/2019/08/05/484410.full AB - Chromatin modifiers act to coordinate gene expression changes critical to neuronal differentiation from neural stem/progenitor cells (NSPCs). Lysine-specific methyltransferase 2D (KMT2D) encodes a histone methyltransferase that promotes transcriptional activation, and is frequently mutated in cancers and in the majority (>70%) of patients diagnosed with the congenital, multisystem intellectual disability (ID) 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.