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

Xuelian He, Liguo Zhang, Luis F. Queme, Xuezhao Liu, Andrew Lu, Ronald R. Waclaw, Xinran Dong, Wenhao Zhou, Grahame Kidd, Sung Ok Yoon, Andres Buonanno, Joshua B. Rubin, Mei Xin, Klaus Armin Nave, Bruce D. Trapp, Michael P. Jankowski, Q. Richard Lu

Research output: Contribution to journalArticle

36 Scopus citations

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.

Original languageEnglish
Pages (from-to)338-351
Number of pages14
JournalNature medicine
Volume24
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint Dive into the research topics of 'A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration'. Together they form a unique fingerprint.

  • Cite this

    He, X., Zhang, L., Queme, L. F., Liu, X., Lu, A., Waclaw, R. R., Dong, X., Zhou, W., Kidd, G., Yoon, S. O., Buonanno, A., Rubin, J. B., Xin, M., Nave, K. A., Trapp, B. D., Jankowski, M. P., & Lu, Q. R. (2018). A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration. Nature medicine, 24(3), 338-351. https://doi.org/10.1038/nm.4483