Abstract
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.
Highlights
Specific patterns of gene expression ensure the proper control of cognitive, behavioral, motor and sensory functions of specialized cells like nerve and glial cells
It has been shown that Schwann cells retain a remarkable plasticity that allows them to dedifferentiate after peripheral nerve injury, shed off the specialized myelin sheath, participate in myelin debris clearance and eventually drive nerve regeneration and re-myelination [2,3]
Axotomy changes Schwann cell morphology from a mature, myelinating phenotype to an immature, regeneration supporting phenotype, a process exactly opposite to that observed during development [16]
Summary
Specific patterns of gene expression ensure the proper control of cognitive, behavioral, motor and sensory functions of specialized cells like nerve and glial cells. It has been shown that Schwann cells (the glial cells of the PNS) retain a remarkable plasticity that allows them to dedifferentiate after peripheral nerve injury, shed off the specialized myelin sheath, participate in myelin debris clearance and eventually drive nerve regeneration and re-myelination [2,3]. The underlying epigenetic mechanisms responsible for this flexibility in regulating gene expression patterns after nerve injury of the PNS remain elusive. Mammalian cells produce a class of non-coding RNAs, microRNAs (miRNAs) in a cell-type-specific manner and utilize them for acute and rapid regulation of gene expression by various mechanisms such as transcriptional gene silencing [4,5], posttranscriptional gene silencing [6,7] and epigenetic modifications [8,9]. MiRNAs function as probes to target multiple mRNAs leading to translational repression or, sometimes, to mRNA degradation [13]
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