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.