An Intrinsic Epigenetic Barrier for Functional Axon Regeneration

Yi-Lan Weng; Ran An; Jessica Cassin; Jessica Joseph; Ruifa Mi; Chen Wang; Chun Zhong; Seung-Gi Jin; Gerd P Pfeifer; Alfonso Bellacosa; Xinzhong Dong; Ahmet Hoke; Zhigang He; Hongjun Song; Guo-Li Ming

doi:10.1016/j.neuron.2017.03.034

An Intrinsic Epigenetic Barrier for Functional Axon Regeneration

Neuron. 2017 Apr 19;94(2):337-346.e6. doi: 10.1016/j.neuron.2017.03.034.

Authors

Yi-Lan Weng¹, Ran An², Jessica Cassin³, Jessica Joseph⁴, Ruifa Mi⁵, Chen Wang⁶, Chun Zhong¹, Seung-Gi Jin⁷, Gerd P Pfeifer⁷, Alfonso Bellacosa⁸, Xinzhong Dong⁹, Ahmet Hoke⁵, Zhigang He⁶, Hongjun Song¹⁰, Guo-Li Ming¹¹

Affiliations

¹ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200040, China.
³ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Pre-doctoral Human Genetics Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁶ F.M. Kirby Neurobiology Center and Department of Neurology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
⁷ Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁸ Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
⁹ The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁰ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Pre-doctoral Human Genetics Training Program, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: shongjun@mail.med.upenn.edu.
¹¹ Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

Mature neurons in the adult peripheral nervous system can effectively switch from a dormant state with little axonal growth to robust axon regeneration upon injury. The mechanisms by which injury unlocks mature neurons' intrinsic axonal growth competence are not well understood. Here, we show that peripheral sciatic nerve lesion in adult mice leads to elevated levels of Tet3 and 5-hydroxylmethylcytosine in dorsal root ganglion (DRG) neurons. Functionally, Tet3 is required for robust axon regeneration of DRG neurons and behavioral recovery. Mechanistically, peripheral nerve injury induces DNA demethylation and upregulation of multiple regeneration-associated genes in a Tet3- and thymine DNA glycosylase-dependent fashion in DRG neurons. In addition, Pten deletion-induced axon regeneration of retinal ganglion neurons in the adult CNS is attenuated upon Tet1 knockdown. Together, our study suggests an epigenetic barrier that can be removed by active DNA demethylation to permit axon regeneration in the adult mammalian nervous system.

Keywords: DNA demethylation; TDG; Tet1; Tet3; axon regeneration; dorsal root ganglion; epigenetic DNA modification.

MeSH terms

5-Methylcytosine / analogs & derivatives
5-Methylcytosine / pharmacology
Animals
Axons / metabolism*
Epigenesis, Genetic* / drug effects
Ganglia, Spinal / cytology*
Ganglia, Spinal / drug effects
Mice, Inbred C57BL
Nerve Regeneration / drug effects*
Nerve Regeneration / physiology*
Peripheral Nerve Injuries / drug therapy
Peripheral Nerve Injuries / pathology*

Substances

5-hydroxymethylcytosine
5-Methylcytosine

Abstract

MeSH terms

Substances

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