Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome.

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 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.

• Authors: 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
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 20 (10 17 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31465303 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chromatin
• DNA-Binding Proteins
• KMT2D protein, human
• Neoplasm Proteins
• Myeloid-Lymphoid Leukemia Protein
• Histone-Lysine N-Methyltransferase
• Kmt2b protein, mouse
• Oxygen

Topics

• Abnormalities, Multiple (genetics, pathology)
• Animals
• Brain (cytology, growth & development)
• Cell Differentiation (genetics)
• Cell Hypoxia (genetics)
• Cell Proliferation (genetics)
• Chromatin (metabolism)
• DNA-Binding Proteins (deficiency, genetics)
• Disease Models, Animal
• Face (abnormalities, pathology)
• Female
• Fibroblasts
• Hematologic Diseases (genetics, pathology)
• Histone-Lysine N-Methyltransferase (deficiency, genetics)
• Humans
• Induced Pluripotent Stem Cells
• Male
• Mice
• Mutation
• Myeloid-Lymphoid Leukemia Protein (deficiency, genetics)
• Neoplasm Proteins (deficiency, genetics)
• Neural Stem Cells (pathology)
• Neurons (pathology)
• Oxygen (metabolism)
• Primary Cell Culture
• RNA-Seq
• Single-Cell Analysis
• Skin (cytology, pathology)
• Vestibular Diseases (genetics, pathology)