Gene Repression By DNA Methylation Promotes Axon Regeneration

Injured peripheral sensory neurons switch to a robust regenerative state after axon injury, yet the roles and mechanisms of gene inactivation after injury are poorly understood (Broude et al., 1997; Smith and Skene, 1997). Here, we show that axon injury in sensory neurons leads to decreased levels of the neural development associated miRNA, miR-9. The miR-9 target UHRF1, a critical epigenetic regulator involved in DNA methylation, increases upon axon injury and is required to promote robust axon regeneration. The level of another target of miR-9, the transcriptional regulator REST, transiently increases after injury and returns towards basal levels by UHRF1-dependent silencing. Mechanistically, UHRF1 interacts with DNMT1 and H3K9me3 to repress REST expression as well as expression of tumor suppressor genes through promoter DNA methylation. In addition, inhibition of DNMT activity impairs axon regeneration after peripheral nerve lesion. Our study suggests an epigenetic mechanism that silences gene expression by DNA methylation to promote axon regeneration. Our study also reveals a mechanism by which neurons recapitulate developmental processes to favor a growth-competent state after injury.

Reference

Broude, E., McAtee, M., Kelley, M.S., and Bregman, B.S. (1997). c-Jun expression in adult rat dorsal root ganglion neurons: differential response after central or peripheral axotomy. Exp Neurol 148, 367-377.

Smith, D.S., and Skene, J.H. (1997). A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth. J Neurosci 17, 646-658.