Combinatorial Action of miRNAs Regulates Transcriptional and Post-Transcriptional Gene Silencing following <em>in</em> <em>vivo</em> PNS Injury

Injury response in the peripheral nervous system (PNS) is characterized by rapid alterations in the genetic program of Schwann cells. However, the epigenetic mechanisms modulating these changes remain elusive. Here we show that sciatic nerve injury in mice induces a cohort of 22 miRNAs, which coordinate Schwann cell differentiation and dedifferentiation through a combinatorial modulation of their positive and negative gene regulators. These miRNAs and their targeted mRNAs form functional complexes with the Argonaute-2 protein to mediate post-transcriptional gene silencing. MiR-138 and miR-709 show the highest affinity amongst the cohort, for binding and regulation of Egr2, Sox-2 and c-Jun expression following injury. Moreover, miR-709 participates in the formation of epigenetic silencing complexes with H3K27me3 and Argonaute-1 to induce transcriptional gene silencing of the Egr2 promoter. Collectively, we identified a discrete cohort of miRNAs as the central epigenetic regulators of the transition between differentiation and dedifferentiation during the acute phase of PNS injury.周围神经系统（peripheral nervous system, PNS）的损伤应答，以施万细胞（Schwann cells）基因程序的快速改变为核心特征。然而，调控此类改变的表观遗传机制仍尚未明确。本研究证实，小鼠坐骨神经损伤可诱导产生22种微小RNA（microRNAs, miRNAs）组成的功能集群，这些miRNAs通过对其正负基因调控因子的组合式调控，协同介导施万细胞的分化与去分化过程。上述miRNAs与其靶信使RNA（messenger RNAs, mRNAs）结合Argonaute-2蛋白形成功能复合物，进而介导转录后基因沉默。在该miRNA集群中，miR-138与miR-709的结合亲和力最高，可在损伤后调控Egr2、Sox-2及c-Jun的表达水平。此外，miR-709可与组蛋白H3赖氨酸27三甲基化（H3K27me3）及Argonaute-1蛋白共同组装为表观遗传沉默复合物，诱导Egr2启动子区域发生转录基因沉默。综上，本研究鉴定出一组独特的miRNA集群，它们是周围神经系统损伤急性期内，细胞分化与去分化转换过程的核心表观遗传调控因子。