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Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination

Nature Neuroscience volume 19, pages 678689 (2016) | Download Citation

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.

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Acknowledgements

Authors would like to thank Z. Ma, Y. Yang and Z. Tao for technical support. We thank J. Wysocka (Stanford University) for Chd7-expressing vectors and comments, E. Hurlock for suggestions, and P. Wight (University of Arkansas) for the Oli-neu cell line. This study was funded in part by grants from the US National Institutes of Health R01NS072427 and R01NS075243 to Q.R.L., the National Multiple Sclerosis Society (NMSS-4727) to Q.R.L., the Foundation for “l'Aide à la Recherche sur la Sclérose en Plaques” (ARSEP), the National Multiple Sclerosis Society grants RG-4318A1/1 and RG-1501-02851 (to C.P. and Q.R.L.), and the program “Investissements d'avenir” ANR-10- IAIHU-06 to C.P.

Author information

Affiliations

  1. Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Danyang He
    • , Chuntao Zhao
    • , Jincheng Wang
    • , Yaqi Deng
    • , Haibo Wang
    • , Xuelian He
    •  & Q Richard Lu
  2. Integrative Biology Graduate Training Program, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Danyang He
    • , Bongwoo Kim
    •  & Q Richard Lu
  3. Sorbonne Universités, UPMC University Paris 06, Inserm U1127, CNRS UMR 7225, GH Pitié-Salpêtrière, Institut du Cerveau et de la Moelle Épinière, ICM, Paris, France.

    • Corentine Marie
    • , Adrien Clavairoly
    • , Magali Frah
    • , Hatem Hmidan
    • , Bernard Zalc
    •  & Carlos Parras
  4. Division of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Blaise V Jones
  5. Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • David Witte
  6. Department of Genetics, The University of Texas Maryland Anderson Cancer Center, Houston, Texas, USA.

    • Xin Zhou
  7. Division of Pediatric Otolaryngology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Daniel I Choo
  8. Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.

    • Donna M Martin
  9. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Donna M Martin
  10. Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.

    • Q Richard Lu

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Contributions

D.H., Q.R.L. and C.P. conceived the studies and designed the experiments. D.H. carried out the studies with Chd7cKO mice and Chd7 target identification and characterization. C.M., M.F. and C.P. performed the studies using Chd7-iKO mice. C.Z. assisted with ChIP-seq experiments. B.K. assisted with histological analysis. J.W. assisted with co-immunoprecipitation experiments. Y.D. and M.F. assisted with LPC-induced demyelination injury. B.V.J. and D.I.C. provided MRI data. D.W. provided human brain samples. X.Z. provided Osterix mutant animals. A.C., H.W., X.H., H.H. and B.Z. provided technical support and intellectual inputs on the manuscript. D.M.M. provided Chd7 floxed mice and advice on the study. D.H., C.P. and Q.R.L. wrote the manuscript with inputs from the other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Carlos Parras or Q Richard Lu.

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https://doi.org/10.1038/nn.4258

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