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

Abstract

SummaryCurrent clinical treatment for neurodegenerative diseases and neural injuries falls short of success, and one primary reason is that neurons in the mammalian central nervous system (CNS) lose their regeneration ability as they mature. Previous studies indicated that the regeneration ability of neurons is governed by complex signaling networks involving many genes. Therefore, here we investigated the roles of Ezh2, a histone methyltransferase, in regulation of mammalian axon regeneration at the epigenetic level. We found that Ezh2 level was gradually downregulated in the mouse nervous system during maturation but significantly upregulated in mature sensory neurons during spontaneous axon regeneration in the peripheral nerve system (PNS), suggesting its role in supporting axon regeneration. Indeed, Ezh2 loss-of-function in sensory neurons impaired PNS axon regeneration in vitro and in vivo. In contrast, overexpression of Ezh2 in retinal ganglion cells in the CNS induced optic nerve regeneration after optic nerve injury in both methyltransferase-dependent and -independent manners. Mechanistic exploration with multiomics sequencing, together with functional analyses, revealed that Ezh2 supported axon regeneration by systematically silencing the transcription of genes regulating synaptic function and axon regeneration inhibitory signaling, while broadly activating factors promoting axon regeneration. Our study not only reveals that Ezh2 coordinates axon regeneration via epigenetically regulating multiple key regenerative pathways, but also suggests that modulating chromatin accessibility is a promising strategy to promote CNS axon regeneration.

X chromosome encoded histone demethylase UTX regulates mammalian axon regeneration via microRNA-124

“…As a result, the level of H3K27me3 was significantly increased after SNI. 50 Together, these data suggested that histone demethylases UTX and JMJD3 might function to suppress axon regeneration. To test this idea, we used our well-established in vivo electroporation technique 51 to co-transfect sensory neurons with a group of 4 different siRNAs against UTX or JMJD3 and the EGFP plasmid.…”

“…As a result, the level of H3K27me3 was significantly increased after SNI. 50 Together, these data suggested that histone demethylases UTX and JMJD3 might function to suppress axon regeneration.…”

Glycogen synthase kinase 3 signaling in neural regeneration in vivo

“…Moreover, PTEN deletion-induced axon regeneration of mature RGCs was attenuated upon Tet1 KD. The histone methyltransferase Ezh2, a potential target of GSK3β ( Ma et al., 2013 ), was also documented to rejuvenate mature CNS neurons at the transcriptomic level by targeting H3K27me3, thus favoring axon regeneration ( Wang et al., 2022 ). However, to date, no direct evidence has shown that GSK3β acts upstream of these epigenetic modifiers to control axon regeneration.…”

Epigenetic Regulation of Optic Nerve Development, Protection, and Repair

“…HATs and HDACs are characterized based on their cellular localization and substrate preference. All these major epigenetic modifications regulate optic nerve development [ 21 ] and recent studies have unraveled their important role in optic nerve protection, regeneration, and repair [ 22 , 23 , 24 , 25 ].…”

“…Moreover, the study also showed inhibition of Ezh2 or G9a is associated with RGC death, thereby cementing the importance of histone methylation patterns in parts of the optic nerve. A recent study also showed that upregulation of Ezh2 is necessary for spontaneous axon regeneration of sensory neurons in different models [ 25 ]. Ezh2 does so by downregulating synaptic function-related genes, including Slc6a13 , which encodes GABA transporter 2.…”