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Expression of regeneration-associated genes is essential to activate the axon regeneration program. Less is known about the contribution of gene inactivation. We reveal an epigenetic mechanism that silences gene expression by ubiquitin-like containing PHD ring finger 1 (UHRF1)-dependent DNA methylation to promote axon regeneration. We suggest that the transient increase in the transcriptional regulator REST, controlled by miR-9 and UHRF1, allows neurons to enter a less mature state that favors a regenerative state. 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