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

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.

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

“…It has become clear that epigenomic changes are important for such reprogramming events, employing mechanisms of gene activation and derepression (Brügger et al 2017; He et al 2018; Hung et al 2015; Jacob 2017; Ma and Svaren 2018). Our previous studies identified the association of trimethylation at Lys27 of histone H3 tail (H3K27me3) at promoters of many genes that become activated after peripheral nerve injury, and we found that the demethylation is required for full activation of some repair genes (Ma et al 2016).…”

STAT3 phosphorylation mediates high glucose—impaired cell autophagy in an HDAC1‐dependent and ‐independent manner in Schwann cells of diabetic peripheral neuropathy

“…In a recent article on the effect of TSA on peripheral neurodegeneration, Kim et al (32) reported that TSA successfully inhibited the phenotypes of peripheral neurodegeneration including myelin fragmentation, axonal degradation, and transdedifferentiation and proliferation of Schwann cells. In addition, He et al (33) found that the inhibition of HDAC3 with RGFP966 or PDA106 increased myelin growth and regeneration after peripheral nerve damage in mice. In line with this, Schwann cell-specific deletion of Hdac3 in mice also enhanced myelin thickness in sciatic nerves.…”

Epigenetic regulation of myelination in health and disease

“…In a recent research, three inhibitors that preferentially target HDAC3, pimelic diphenylamide compound 106 (PDA106), RGFP966, and apicidin, were found to markedly elevate the expression of early growth response 2 (EGR2) in developing SCs, which is a key promyelinating regulator and serves an indicator of myelinogenic potential. Besides, treatment with HDAC3 inhibitors resulted in an expansion of cellular processes, actin cytoskeleton augmentation and induction of myelin protein expression in vitro (He et al., ). Sustained ablation of Hdac3 in developing immature or pre‐myelinating SCs mimics the effect of HDAC3 inhibitors and results in myelin sheath overgrowth and hypermyelination in the mice.…”

“…In a recent study, HDAC3 was revealed to pair with P300 histone acetyltransferase in differentiating SCs and target a set of genes that coincide with enhancer elements marked by H3K27ac (histone H3 lysine27 acetylation; He et al., ). This observation posits HDAC3/P300 coordination at the apex of a gene regulatory network that controls both activation and inhibition of SCs myelination via distinct mechanisms.…”

“…Importantly, after peripheral nerve transection, HDAC3 inhibitors can enhance both histological remyelination and functional recovery of nerve conduction in adult mice (He et al., ). These results were further identified in Hdac3 deletion mice, indicating that ablation Hdac3 before and after injury enhances SC remyelination, thus point to the potential beneficial effect of controlled HDAC3 inhibition for peripheral myelin repair.…”