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.

中文翻译：

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组蛋白脱乙酰酶 3 依赖性通路限制外周髓鞘生长和功能再生。

雪旺细胞介导的髓鞘再生缺陷会损害神经损伤后的功能恢复，从而导致周围神经病变。调节髓鞘再生阻滞的机制仍然难以捉摸。在这里，通过针对表观遗传调节剂的小分子筛选，我们将组蛋白脱乙酰酶 3（HDAC3；一种组蛋白修饰酶）鉴定为外周髓鞘生成的有效抑制剂。抑制 HDAC3 可增强髓鞘的生长和再生，并改善小鼠周围神经损伤后的功能恢复。HDAC3 拮抗髓鞘生成神经调节蛋白-PI3K-AKT 信号轴。而且，全基因组分析显示，HDAC3 通过表观遗传沉默抑制髓鞘形成前程，同时与 p300 组蛋白乙酰转移酶协调激活髓鞘形成抑制程序，包括 HIPPO 信号效应子 TEAD4 以抑制髓鞘生长。小鼠中 Hdac3 或 Tead4 雪旺细胞特异性缺失导致坐骨神经髓鞘厚度增加。因此，我们的研究结果将 HDAC3-TEAD4 网络确定为细胞内在抑制机制的双重功能开关，可对抗髓鞘生成信号并维持外周髓鞘稳态，突出了瞬时 HDAC3 抑制改善外周髓鞘修复的治疗潜力。小鼠中 Hdac3 或 Tead4 雪旺细胞特异性缺失导致坐骨神经髓鞘厚度增加。因此，我们的研究结果将 HDAC3-TEAD4 网络确定为细胞内在抑制机制的双重功能开关，可对抗髓鞘生成信号并维持外周髓鞘稳态，突出了瞬时 HDAC3 抑制改善外周髓鞘修复的治疗潜力。小鼠中 Hdac3 或 Tead4 雪旺细胞特异性缺失导致坐骨神经髓鞘厚度增加。因此，我们的研究结果将 HDAC3-TEAD4 网络确定为细胞内在抑制机制的双重功能开关，可对抗髓鞘生成信号并维持外周髓鞘稳态，突出了瞬时 HDAC3 抑制改善外周髓鞘修复的治疗潜力。