Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via regulation of key regenerative pathways
Xue-Wei Wang, … , Chang-Mei Liu, Feng-Quan Zhou
Xue-Wei Wang, … , Chang-Mei Liu, Feng-Quan Zhou
Published November 28, 2023
Citation Information: J Clin Invest. 2024;134(3):e163145. https://doi.org/10.1172/JCI163145.
View: Text | PDF
Research Article Neuroscience Ophthalmology

Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via regulation of key regenerative pathways

Abstract

Current treatments for neurodegenerative diseases and neural injuries face major challenges, primarily due to the diminished regenerative capacity of neurons in the mammalian CNS as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulating mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons following peripheral nerve injury to facilitate spontaneous axon regeneration. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation–dependent and –independent mechanisms. Further investigation revealed that Ezh2 fostered axon regeneration by orchestrating the transcriptional silencing of genes governing synaptic function and those inhibiting axon regeneration, while concurrently activating various factors that support axon regeneration. Notably, we demonstrated that GABA transporter 2, encoded by Slc6a13, acted downstream of Ezh2 to control axon regeneration. Overall, our study underscores the potential of modulating chromatin accessibility as a promising strategy for promoting CNS axon regeneration.

Authors

Xue-Wei Wang, Shu-Guang Yang, Ming-Wen Hu, Rui-Ying Wang, Chi Zhang, Anish R. Kosanam, Arinze J. Ochuba, Jing-Jing Jiang, Ximei Luo, Yun Guan, Jiang Qian, Chang-Mei Liu, Feng-Quan Zhou

×

Figure 1

Ezh2 is developmentally downregulated in the nervous system and upregulated in DRG neurons following peripheral nerve injury.

Options: View larger image (or click on image) Download as PowerPoint
Ezh2 is developmentally downregulated in the nervous system and upregula...
(A and B) Representative immunoblotting showing that Ezh2 is developmentally downregulated in the DRG (A) and cerebral cortex (B). (C) Immunoblotting showing that Ezh2 is significantly increased in L4/5 DRGs 3 days after sciatic nerve transection. (D) Quantification of relative protein levels of Ezh2 in A (n = 2 independent experiments). (E) Quantification of relative protein levels of Ezh2 in B (1-way ANOVA followed by Tukey’s multiple comparisons; P 0.0001; n = 3 independent experiments). (F) Quantification of relative protein levels of Ezh2 in C (unpaired, 2-tailed t test; P = 0.0092; n = 3 for sham, n = 5 for sciatic nerve transection). (G) Representative immunofluorescence of DRG sections showing increased H3K27me3 levels in nuclei of DRG neurons 1 or 3 days after sciatic nerve transection. DRG sections were stained with anti-H3K27me3 (green) and anti-β-tubulin III (red). The rightmost column displays enlarged images of the areas outlined in white, dashed boxes. Yellow arrows indicate H3K27me3 in nuclei of DRG neurons. Scale bars: 100 μm, 30 μm for enlarged images. (H) Quantification of fluorescence intensity of H3K27me3 immunoreactivity in DRG neurons in G (1-way ANOVA followed by Tukey’s multiple comparisons; P 0.0001; n = 3 mice for all). SNT, sciatic nerve transection. **P 0.01, ***P 0.001, ****P 0.0001.