RT Journal Article
SR Electronic
T1 Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 484410
DO 10.1101/484410
A1 Giovanni A. Carosso
A1 Leandros Boukas
A1 Jonathan J. Augustin
A1 Ha Nam Nguyen
A1 Briana L. Winer
A1 Gabrielle H. Cannon
A1 Johanna D. Robertson
A1 Li Zhang
A1 Kasper D. Hansen
A1 Loyal A. Goff
A1 Hans T. Bjornsson
YR 2019
UL http://biorxiv.org/content/early/2019/08/05/484410.abstract
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.