Abstract
Mutations in CHD7, encoding ATP-dependent chromodomain helicase DNA-binding protein 7, in CHARGE syndrome lead to multiple congenital anomalies, including craniofacial malformations, neurological dysfunction and growth delay. Mechanisms underlying the CNS phenotypes remain poorly understood. We found that Chd7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1 and is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses in mice, coupled with transcriptome profiling, revealed that Chd7 interacted with Sox10 and targeted the enhancers of key myelinogenic genes. These analyses identified previously unknown Chd7 targets, including bone formation regulators Osterix (also known as Sp7) and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, Chd7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages, including oligodendrocytes and osteoblasts, pointing to previously uncharacterized Chd7 functions in white matter pathogenesis in CHARGE syndrome.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic-Leucine Zipper Transcription Factors
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CHARGE Syndrome / physiopathology*
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DNA Helicases / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Gene Expression Profiling
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Gene Expression Regulation, Developmental / physiology*
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Mice
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Mice, Knockout
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Mutation
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Myelin Sheath / physiology*
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Nerve Tissue Proteins / genetics
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Neurogenesis / physiology*
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Nuclear Proteins / genetics
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Oligodendrocyte Transcription Factor 2
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Oligodendroglia / metabolism
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Oligodendroglia / physiology
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SOXE Transcription Factors / metabolism
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SOXE Transcription Factors / physiology*
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Sp7 Transcription Factor
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Basic-Leucine Zipper Transcription Factors
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Chd7 protein, mouse
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Creb3l2 protein, mouse
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DNA-Binding Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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Olig2 protein, mouse
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Oligodendrocyte Transcription Factor 2
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SOXE Transcription Factors
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Sox10 protein, mouse
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Sp7 Transcription Factor
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Sp7 protein, mouse
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Transcription Factors
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Smarca4 protein, mouse
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DNA Helicases