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A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

Nature Medicine volume 24, pages 338351 (2018) | Download Citation

Abstract

Deficits in Schwann cell–mediated remyelination impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms mediating block of remyelination remain elusive. Here, through small-molecule screening focusing on epigenetic modulators, we identified histone deacetylase 3 (HDAC3; a histone-modifying enzyme) as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 enhanced myelin growth and regeneration and improved functional recovery after peripheral nerve injury in mice. HDAC3 antagonizes the myelinogenic neuregulin–PI3K–AKT signaling axis. Moreover, genome-wide profiling analyses revealed that HDAC3 represses promyelinating programs through epigenetic silencing while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include the HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann cell–specific deletion of either Hdac3 or Tead4 in mice resulted in an elevation of myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3–TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.

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Acknowledgements

We thank M. Wegner, J. Wells, and E. Hurlock for critical reading of the manuscript. We are grateful to E. Olson (University of Texas Southwestern Medical Center), D. Meijer (University of Edinburgh), and M. Wegner (Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)) for Hdac3-floxed mice, Dhh-Cre mice, and antibodies against EGR2 and KROX20, respectively, and to N. Wu and L. Xu for technical support. This study was funded in part by the US National Institutes of Health (NIH; grant no. R37NS096359 and R01NS075243 to Q.R.L.; R35NS097303 to B.D.T.; and R01AR064551-01A1 to M.P.J.) and the National Multiple Sclerosis Society (grant no. NMSS-RG1507 to Q.R.L.).

Author information

Author notes

    • Xuelian He
    •  & Liguo Zhang

    These authors contributed equally to this work.

Affiliations

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

    • Xuelian He
    • , Liguo Zhang
    • , Luis F Queme
    • , Xuezhao Liu
    • , Andrew Lu
    • , Ronald R Waclaw
    • , Mei Xin
    • , Michael P Jankowski
    •  & Q Richard Lu
  2. Department of Anesthesia Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

    • Luis F Queme
    •  & Michael P Jankowski
  3. Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.

    • Xinran Dong
    • , Wenhao Zhou
    •  & Q Richard Lu
  4. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Grahame Kidd
    •  & Bruce D Trapp
  5. Department of Biological Chemistry & Pharmacology, Ohio State University, Columbus, Ohio, USA.

    • Sung-Ok Yoon
  6. Section on Molecular Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

    • Andres Buonanno
  7. Departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Joshua B Rubin
  8. Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

    • Klaus-Armin Nave

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Contributions

X.H., L.Z., and Q.R.L. designed the experiments, analyzed the data, and wrote the manuscript with input from all authors. L.F.Q. and M.P.J. carried out CMAP analysis. X.H., L.Z., X.L., A.L., G.K., and X.D. performed the in vitro, in vivo, gene profiling, ChIP–seq, and in silico analyses. R.R.W., W.Z., S.-O.Y., J.B.R., M.X., K.-A.N., and B.D.T. provided resources and inputs. A.B. and K.N. provided floxed Tead4 and Cnp-Cre animals, respectively. Q.R.L. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Q Richard Lu.

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    Supplementary Table 1

    Transcription Factor loci with chromatin co-occupancy of HDAC3 and p300

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DOI

https://doi.org/10.1038/nm.4483