Abstract
Chromatin modifiers act to coordinate gene expression changes critical to neuronal differentiation from neural progenitor cells (NPCs). 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). While critical roles for KMT2D are established in various non-neuronal tissues, 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-dependent functions in neurodevelopmental contexts, including adult-born hippocampal neural stem cells (NSCs) and NPCs in vivo. We report cell-autonomous defects in proliferation, cell cycle, and cell survival, accompanied by NSC depletion and precocious differentiation of NPCs in vitro and in vivo. Transcriptional suppression in KMT2D-deficient cells indicated perturbation of hypoxia-responsive cellular metabolism pathways, and functional experiments confirmed abnormalities of neuronal hypoxia response in cells with inactivated KMT2D. Together, our findings support a model in which loss of KMT2D function suppresses expression of oxygen-responsive gene programs in developing neural progenitors, resulting in precocious neuronal differentiation and exhaustion of the adult-born hippocampal progenitor pool.