Chernov Andrei V, Shubayev Veronica I
Department of Anesthesiology, University of California, San Diego, San Diego, CA, United States.
VA San Diego Healthcare System, San Diego, CA, United States.
Front Mol Neurosci. 2022 Aug 2;15:958568. doi: 10.3389/fnmol.2022.958568. eCollection 2022.
The convergence of transcriptional and epigenetic changes in the peripheral nervous system (PNS) reshapes the spatiotemporal gene expression landscape in response to nerve transection. The control of these molecular programs exhibits sexually dimorphic characteristics that remain not sufficiently characterized. In the present study, we recorded genome-wide and sex-dependent early-phase transcriptional changes in regenerating (proximal) sciatic nerve 24 h after axotomy. Male nerves exhibited more extensive transcriptional changes with male-dominant upregulation of cytoskeletal binding and structural protein genes. Regulation of mRNAs encoding ion and ionotropic neurotransmitter channels displayed prominent sexual dimorphism consistent with sex-specific mRNA axonal transport in an early-phase regenerative response. Protein kinases and axonal transport genes showed sexually dimorphic regulation. Genes encoding components of synaptic vesicles were at high baseline expression in females and showed post-injury induction selectively in males. Predictive bioinformatic analyses established patterns of sexually dimorphic regulation of neurotrophic and immune genes, including activation of glial cell line-derived neurotrophic factor Gfra1 receptor and immune checkpoint cyclin D1 (Ccnd1) potentially linked to X-chromosome encoded tissue inhibitor of matrix metallo proteinases 1 (Timp1). Regulatory networks involving Olig1, Pou3f3/Oct6, Myrf, and Myt1l transcription factors were linked to sex-dependent reprogramming in regenerating nerves. Differential expression patterns of non-coding RNAs motivate a model of sexually dimorphic nerve regenerative responses to injury determined by epigenetic factors. Combined with our findings in the corresponding dorsal root ganglia (DRG), unique early-phase sex-specific molecular triggers could enrich the mechanistic understanding of peripheral neuropathies.
外周神经系统（PNS）中转录和表观遗传变化的汇聚重塑了时空基因表达格局，以应对神经横断损伤。这些分子程序的控制表现出性别二态性特征，但仍未得到充分表征。在本研究中，我们记录了轴突切断后24小时再生（近端）坐骨神经中全基因组和性别依赖性的早期转录变化。雄性神经表现出更广泛的转录变化，细胞骨架结合和结构蛋白基因以雄性为主上调。编码离子和离子型神经递质通道的mRNA的调控显示出明显的性别二态性，这与早期再生反应中性别特异性的mRNA轴突运输一致。蛋白激酶和轴突运输基因表现出性别二态性调控。编码突触小泡成分的基因在雌性中基线表达较高，损伤后仅在雄性中选择性诱导。预测性生物信息学分析确定了神经营养和免疫基因的性别二态性调控模式，包括胶质细胞源性神经营养因子Gfra1受体和免疫检查点细胞周期蛋白D1（Ccnd1）的激活，这可能与X染色体编码的基质金属蛋白酶1组织抑制剂（Timp1）有关。涉及Olig1、Pou3f3/Oct6、Myrf和Myt1l转录因子的调控网络与再生神经中的性别依赖性重编程有关。非编码RNA的差异表达模式提示了一种由表观遗传因素决定的对损伤的性别二态性神经再生反应模型。结合我们在相应背根神经节（DRG）中的发现，独特的早期性别特异性分子触发因素可以丰富对外周神经病变机制的理解。
