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

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Figure 8

Ezh2 overexpression enhances optic nerve regeneration by transcriptionally suppressing Lingo3 and Omg.

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Ezh2 overexpression enhances optic nerve regeneration by transcriptiona...
(A) Top: Experimental timeline. Bottom: Representative images of optic nerves showing that Lingo3 or Omg overexpression almost completely blocks Ezh2 overexpression-induced optic nerve regeneration. Columns on the right display enlarged images of the areas in white, dashed boxes on the left, showing axons at 250, 500, 750, and 1,000 μm distal to the crush sites, which are aligned with the yellow line. Yellow arrows indicate longest axons in each nerve. Scale bars: 100 μm, 50 μm for enlarged images. (B) Quantification of optic nerve regeneration in A (1-way ANOVA followed by Tukey’s multiple comparisons; P 0.0001 at 250, 500, 750, 1,000, and 1,250 μm, P = 0.0003 at 1,500 μm; n = 10 mice for control and Lingo3 overexpression, n = 9 mice for Ezh2 and Lingo3 cooverexpression, n = 7 mice for others). (C) CUTTag followed by qPCR showing H3K27me3 enrichment in the promoter region of Lingo3, but not that of Omg (paired 2-tailed t test; P = 0.0197 between negative control and Lingo3 R1, P = 0.1010 between negative control and Omg R1, P = 0.2329 between negative control and Omg R2; n = 3 independent experiments). Note that the negative control and positive control are identical to those in Figure 6A. *P 0.05, **P 0.01, ***P 0.001, ****P 0.0001.