miRNA-9 regulates axon regeneration through the transcriptional regulator REST and the epigenetic factor UHRF1 [miRNA array]. Mus musculus

Injured sensory neurons successfully activate a pro-regenerative transcriptional program to enable axon regeneration and functional recovery, but the roles of genes that are inactivated after injury remain poorly understood. Analysis of the miRNA expression profile triggered by axon injury revealed down-regulation of the neural development associated miRNA, miR-9. A target of miR-9 is the critical epigenetic regulator involved in DNA methylation, ubiquitin-like containing PHD ring finger 1 (UHRF1), which increased after injury to promote axon regeneration. UHRF1 is known to repress the transcription of tumor suppressor genes through DNA methylation and we show that UHRF1 interacts with DNMT1 to methylate the promoter region of the tumor suppressors PTEN and CDKN1A, thereby triggering their inactivation. We also reveal that UHRF1 represses the transcriptional regulator REST. Our findings define an epigenetic mechanism that silences the transcription of axon growth suppressors to promote axon regeneration in sensory neurons. Overall design: miRNA expression profiling of spot cultures collected at Day in Vitro (DIV) 7, axotomized spot cultures at DIV7 collected at 1 hour, 3 hour, or 8 hours post injury.