Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration

Proc Natl Acad Sci U S A. 2018 Dec 26;115(52):E12417-E12426. doi: 10.1073/pnas.1812518115. Epub 2018 Dec 10.

Abstract

Injured peripheral sensory neurons switch to a regenerative state after axon injury, which requires transcriptional and epigenetic changes. However, the roles and mechanisms of gene inactivation after injury are poorly understood. Here, we show that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. Ubiquitin-like containing PHD ring finger 1 (UHRF1), a critical epigenetic regulator involved in DNA methylation, increases upon axon injury and is required for robust axon regeneration. The increased level of UHRF1 results from a decrease in miR-9. The level of another target of miR-9, the transcriptional regulator RE1 silencing transcription factor (REST), transiently increases after injury and is required for axon regeneration. Mechanistically, UHRF1 interacts with DNA methyltransferases (DNMTs) and H3K9me3 at the promoter region to repress the expression of the tumor suppressor gene phosphatase and tensin homolog (PTEN) and REST. Our study reveals an epigenetic mechanism that silences tumor suppressor genes and restricts REST expression in time after injury to promote axon regeneration.

Keywords: DNMT; REST; UHRF1; axon regeneration; epigenetic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axons / metabolism
  • Axons / physiology
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • DNA Methylation / genetics
  • Epigenesis, Genetic / genetics
  • Epigenomics / methods
  • Female
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Silencing / physiology
  • Histones / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Regeneration / genetics*
  • Nerve Regeneration / physiology
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / physiology*
  • Promoter Regions, Genetic / genetics
  • Repressor Proteins / metabolism
  • Sciatic Nerve / injuries
  • Ubiquitin-Protein Ligases

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Histones
  • Nuclear Proteins
  • RE1-silencing transcription factor
  • Repressor Proteins
  • Ubiquitin-Protein Ligases
  • Uhrf1 protein, mouse