TY - JOUR
T1 - Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome
AU - Carosso, Giovanni A.
AU - Boukas, Leandros
AU - Augustin, Jonathan J.
AU - Nguyen, Ha Nam
AU - Winer, Briana L.
AU - Cannon, Gabrielle H.
AU - Robertson, Johanna D.
AU - Zhang, Li
AU - Hansen, Kasper D.
AU - Goff, Loyal A.
AU - Bjornsson, Hans T.
N1 - Funding Information:
HTB is funded through an Early Independence Award from the NIH (DP5OD017877), the Icelandic Research Fund (195835-051), and the Louma G. Foundation. Imaging was performed with NIH support (S10OD016374). The karyotype facility was supported by the National Institute of Child Health and Human Development (1U54 HD079123-01A1). FACS was performed at the Bloomberg School of Public Health. We thank Michael Sherman for assistance with image quantification and Manisha Aggarwal for MRI. Schematics were created by Mark Sandusky or with Biorender.com. Hongjun Song and Kai Ge provided critical reagents and advice. Hal Dietz and Gregg Semenza provided conceptual guidance.
Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/10/17
Y1 - 2019/10/17
N2 - 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=85078166835&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078166835&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.129375
DO - 10.1172/jci.insight.129375
M3 - Article
C2 - 31465303
AN - SCOPUS:85078166835
VL - 4
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 20
M1 - e129375
ER -