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.).
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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.
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Transcription Factor loci with chromatin co-occupancy of HDAC3 and p300 (XLSX 13 kb)
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He, X., Zhang, L., Queme, L. et al. A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration. Nat Med 24, 338–351 (2018). https://doi.org/10.1038/nm.4483
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DOI: https://doi.org/10.1038/nm.4483
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