Role of Myc Proto-Oncogene as a Transcriptional Hub to Regulate the Expression of Regeneration-Associated Genes following Preconditioning Peripheral Nerve Injury

The Journal of Neuroscience, 2021 · DOI: https://doi.org/10.1523/JNEUROSCI.1745-20.2020 · Published: January 20, 2021

Regenerative Medicine Neurology Genetics

Simple Explanation

This study investigates how preconditioning nerve injury enhances nerve regeneration. It identifies Myc proto-oncogene as a key regulator of regeneration-associated genes (RAGs). The research shows that Myc binds to the promoters of certain RAGs, like Jun and Atf3, increasing their expression after a preconditioning injury. Furthermore, DNA methylation plays a role in activating Myc, which in turn influences axon regeneration after spinal cord injury.

Study Duration

Not specified

Participants

Adult female Sprague Dawley rats weighing 250-300 g and Myc floxed mice

Evidence Level

Not specified

Key Findings

1
Myc proto-oncogene functions as a transcriptional hub gene regulating a subset of regeneration-associated genes (RAGs) in DRGs following preconditioning injury.
2
c-MYC binds to the promoters of RAGs like Jun, Atf3, and Sprr1a, with Myc upregulation preceding RAG upregulation.
3
Myc overexpression in DRGs significantly prevents sensory axon retraction after spinal cord injury, dependent on its downstream RAG, June.

Research Summary

This study identifies Myc as a transcriptional hub regulating regeneration-associated genes (RAGs) after preconditioning nerve injury. The research demonstrates that Myc binds to RAG promoters, and its activation is linked to DNA methylation. Myc overexpression prevents axon retraction following spinal cord injury, highlighting its role in axon regeneration.

Practical Implications

Therapeutic Potential

Combinatorial overexpression of upstream hub regulators could induce sequential activation of downstream transcription factors, leading to the upregulation of a whole complement of RAGs.

Understanding Regeneration

Identification of more upstream hub transcription factors and the epigenetic mechanisms specific for individual hub TFs would advance our understanding of how the preconditioning injury induces orchestrated upregulation of RAGs.

Combinatorial Genetic Approaches

Dissecting out the hierarchical relationship among upstream hub TFs in the induction of RAGs should provide clues for selecting optimal TF combinations with efficient synergism to achieve more meaningful and robust axon regeneration.

Study Limitations

1
The custom PCR array covered only 44 RAGs, limiting the scope of analysis.
2
The methylation assay was done using whole DRGs containing many non-neural cells.
3
Axonal growth across the lesion site may require activation of other RAGs that are Myc-independent.

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