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

Young Mi Oh, Marcus Mahar, Eric E. Ewan, Kathleen M. Leahy, Guoyan Zhao, Valeria Cavalli

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish
Pages (from-to)E12417-E12426
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number52
DOIs
StatePublished - Dec 26 2018

Keywords

  • Axon regeneration
  • DNMT
  • Epigenetic
  • REST
  • UHRF1

Fingerprint

Dive into the research topics of 'Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration'. Together they form a unique fingerprint.

Cite this