Rxivist logo

Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome

By Giovanni A. Carosso, Leandros Boukas, Jonathan J Augustin, Ha Nam Nguyen, Briana L Winer, Gabrielle H. Cannon, Johanna D. Robertson, Li Zhang, Kasper D Hansen, Loyal A. Goff, Hans T Bjornsson

Posted 02 Dec 2018
bioRxiv DOI: 10.1101/484410 (published DOI: 10.1172/jci.insight.129375)

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. ![Figure][1]</img> [1]: pending:yes

Download data

  • Downloaded 1,536 times
  • Download rankings, all-time:
    • Site-wide: 8,582 out of 116,126
    • In neuroscience: 1,003 out of 18,529
  • Year to date:
    • Site-wide: 14,555 out of 116,126
  • Since beginning of last month:
    • Site-wide: 23,460 out of 116,126

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide


Sign up for the Rxivist weekly newsletter! (Click here for more details.)