Role of Myc proto-oncogene as a transcriptional hub to regulate the expression of regeneration-associated genes following preconditioning peripheral nerve injury.

Preconditioning peripheral nerve injury enhances the intrinsic growth capacity of dorsal root ganglia (DRG) sensory axons by inducing transcriptional upregulation of the regeneration-associated genes (RAGs). However, it is still unclear how preconditioning injury leads to the orchestrated induction of many RAGs. The present study identified Myc proto-oncogene as a transcriptional hub gene to regulate the expression of a distinct subset of RAGs in DRGs following the preconditioning injury. We demonstrated that c-MYC bound to the promoters of certain RAGs such as Jun, Atf3, and Sprr1a and that Myc upregulation following SNI preceded that of the RAGs bound by c-MYC. Marked DNA methylation of the Myc exon 3 sequences was implicated in the early transcriptional activation and accompanied by open histone marks. Myc deletion led to a decrease in the injury-induced expression of a distinct subset of RAGs, which were highly overlapped with the list of RAGs that were upregulated by Myc overexpression. Following dorsal hemisection spinal cord injury in female rats, Myc overexpression in DRGs significantly prevented the retraction of the sensory axons in a manner dependent on its downstream RAG, Jun. Our results suggest that Myc plays a critical role in axon regeneration via its transcriptional activity to regulate the expression of a spectrum of downstream RAGs and subsequent effector molecules. Identification of more upstream hub TFs and the epigenetic mechanisms specific for individual hub TFs would advance our understanding of how the preconditioning injury induces orchestrated upregulation of RAGs.SIGNIFICANCE STATEMENTIdentification of the transcriptional network regulating RAG expression would enable us to understand how preconditioning injury enhances intrinsic regeneration capacity. It has been suggested that a handful of hub transcription factors may play an important role in regulating the expression of a large set of RAGs. However, the precise roles of the hub genes in the transcriptional activation of RAGs have not been verified. This study provides experimental evidence that Myc proto-oncogen functions as a transcriptional hub gene and that the DNA methylation may lead to early transcriptional activation of Myc. Dissecting out the hub transcription factors and their hierarchical relationship should provide important clues on the combinatorial genetic approaches to achieve more meaningful and robust axon regeneration.