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Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome

View ORCID ProfileGiovanni 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
doi: https://doi.org/10.1101/484410
Giovanni A. Carosso
1Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
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  • ORCID record for Giovanni A. Carosso
Leandros Boukas
1Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
3Department of Biostatistics, Johns Hopkins University School of Medicine, Baltimore, United States
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Jonathan J. Augustin
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
4Predoctoral Training Program in Biochemistry, Cellular, and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, United States
5Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
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Ha Nam Nguyen
6Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States
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Briana L. Winer
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
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Gabrielle H. Cannon
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
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Johanna D. Robertson
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
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Li Zhang
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
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Kasper D. Hansen
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
3Department of Biostatistics, Johns Hopkins University School of Medicine, Baltimore, United States
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Loyal A. Goff
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
5Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, United States
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Hans T. Bjornsson
2McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, United States
7Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, United States
8Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
9Landspitali University Hospital, Reykjavik, Iceland
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  • For correspondence: hbjorns1@jhmi.edu
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Abstract

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.

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  • Conflict of interest: The authors declare no conflict of interest.

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Posted August 05, 2019.
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Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome
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
bioRxiv 484410; doi: https://doi.org/10.1101/484410
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Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome
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
bioRxiv 484410; doi: https://doi.org/10.1101/484410

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