TY - JOUR AU - Carosso, Giovanni A. AU - Boukas, Leandros AU - Augustin, Jonathan J. AU - Nguyen, Ha Nam AU - Winer, Briana L. AU - Cannon, Gabrielle H. AU - Robertson, Johanna D. AU - Zhang, Li AU - Hansen, Kasper D. AU - Goff, Loyal A. AU - Bjornsson, Hans T. T1 - Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome PY - 2019/10/17/ 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 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.129375 VL - 4 IS - 20 UR - https://doi.org/10.1172/jci.insight.129375 PB - The American Society for Clinical Investigation ER -