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

• Published in: Nature medicine Vol. 24; no. 3; pp. 338 - 351
• Main Authors: He, Xuelian, Zhang, Liguo, Queme, Luis F, Liu, Xuezhao, Lu, Andrew, Waclaw, Ronald R, Dong, Xinran, Zhou, Wenhao, Kidd, Grahame, Yoon, Sung-Ok, Buonanno, Andres, Rubin, Joshua B, Xin, Mei, Nave, Klaus-Armin, Trapp, Bruce D, Jankowski, Michael P, Lu, Q Richard
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2018; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/109; 13/51; 13/89; 14/1; 14/19; 14/28; 38/1; 38/89; 49/15; 49/91; 631/378/2584/1695; 631/378/2606; 64/60; AKT protein; Animals; Biomedicine; Cancer Research; Chromatin; Clonal deletion; DNA-Binding Proteins - genetics; E1A-Associated p300 Protein - genetics; Enzyme inhibitors; Epigenetics; Event-related potentials; Genetic aspects; Genome; Genomes; Health aspects; Histone acetyltransferase; Histone deacetylase; Histone Deacetylases; Homeostasis; Humans; Infectious Diseases; Machinery and equipment; Metabolic Diseases; Mice; Mice, Transgenic; Modulators; Molecular Medicine; Muscle Proteins - genetics; Myelin; Myelin proteins; Myelin Sheath - genetics; Myelin Sheath - metabolism; Myelination; Nerve Degeneration - genetics; Nerve Degeneration - physiopathology; Nerve regeneration; Nerve Regeneration - genetics; Nerves; Neuregulin; Neuromodulation; Neurosciences; Peripheral Nerve Injuries - genetics; Peripheral Nerve Injuries - physiopathology; Peripheral Nerve Injuries - rehabilitation; Peripheral nerves; Recovery of function; Recovery of Function - genetics; Regeneration; Remyelination - genetics; Restoration; Schwann Cells - metabolism; Schwann Cells - pathology; Sciatic Nerve - growth & development; Sciatic Nerve - injuries; Sciatic Nerve - metabolism; Signal Transduction; Signaling; TEA Domain Transcription Factors; Transcription Factors - genetics
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4483

Screening for small-molecule epigenetic modulators identifies HDAC3 inhibitors that promote peripheral myelin repair after nerve injury in rodents.
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.