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

Autor:	Oh YM; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110., Mahar M; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110., Ewan EE; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110., Leahy KM; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110., Zhao G; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110., Cavalli V; Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110; cavalli@wustl.edu.; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110.; Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Dec 26; Vol. 115 (52), pp. E12417-E12426. Date of Electronic Publication: 2018 Dec 10.
DOI:	10.1073/pnas.1812518115
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu