A Histone Deacetylase 3-Dependent Pathway Delimits Peripheral Myelin Growth and Functional Regeneration [RNA-seq]

Schwann cell remyelination defects impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms that mediate remyelination block remain elusive. Upon small-molecule epigenetic screening, we identified HDAC3, a histone-modifying enzyme, as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 markedly enhances myelin growth and regeneration, and improves functional recovery after peripheral nerve injury. HDAC3 antagonizes myelinogenic neuregulin/PI3K/AKT signaling axis. Moreover, genome-wide profiling analyses reveal that HDAC3 represses pro-myelinating programs through epigenetic silencing, while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann-cell-specific deletion of either Hdac3 or Tead4 results in a profound increase in 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. 4 RNA-Seq samples from P6 sciatic nerves of Ctrl and Hdac3-cKO mice (Cnpcre-Ctrl, Cnpcre-cKO, Dhhcre-Ctrl, Dhhcre-cKO)施万细胞（Schwann cell）的髓鞘再生缺陷会损害神经损伤后的功能恢复，进而引发周围神经病。目前介导髓鞘再生阻滞的机制仍不明确。通过小分子表观遗传筛选，我们鉴定出组蛋白去乙酰化酶3（HDAC3）——一种组蛋白修饰酶——是周围髓鞘生成的强效抑制剂。抑制HDAC3可显著促进髓鞘生长与再生，并改善周围神经损伤后的功能恢复。HDAC3可拮抗促髓鞘形成的神经调节蛋白/PI3K/AKT信号轴。此外，全基因组图谱分析显示，HDAC3通过表观遗传沉默抑制促髓鞘形成程序，同时与p300组蛋白乙酰转移酶协同激活髓鞘生成抑制性程序，其中包括通过HIPPO信号通路效应因子TEAD4来抑制髓鞘生长。在施万细胞中特异性敲除Hdac3或Tead4，可导致坐骨神经的髓鞘厚度显著增加。因此，本研究发现HDAC3-TEAD4网络作为细胞内源性抑制机制的双功能开关，可拮抗促髓鞘形成信号并维持周围髓鞘稳态，这凸显了暂时性抑制HDAC3以改善周围髓鞘修复的治疗潜力。本数据集包含来自P6龄小鼠坐骨神经的4份RNA测序（RNA-Seq）样本，涉及对照组（Ctrl）与Hdac3条件性敲除（Hdac3-cKO）小鼠（包括Cnpcre-Ctrl、Cnpcre-cKO、Dhhcre-Ctrl、Dhhcre-cKO四组）。