Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural Regeneration
Abstract Epigenetic regulation of neuronal transcriptomic landscape is emerging to be a key coordinator of mammalian neural regeneration. The roles of two histone 3 lysine 27 (H3K27) demethylases, Kdm6a/b, in controlling neuroprotection and axon regeneration are investigated here. Deleting either Kd...
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202405537 |
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| author | Shu‐Guang Yang Chang‐Ping Li Xue‐Wei Wang Tao Huang Cheng Qian Qiao Li Ling‐Rui Zhao Si‐Yu Zhou Chen‐Yun Ding Rui Nie Saijilafu Yu‐Cai Hong Chang‐Mei Liu Feng‐Quan Zhou |
| author_facet | Shu‐Guang Yang Chang‐Ping Li Xue‐Wei Wang Tao Huang Cheng Qian Qiao Li Ling‐Rui Zhao Si‐Yu Zhou Chen‐Yun Ding Rui Nie Saijilafu Yu‐Cai Hong Chang‐Mei Liu Feng‐Quan Zhou |
| author_sort | Shu‐Guang Yang |
| collection | DOAJ |
| description | Abstract Epigenetic regulation of neuronal transcriptomic landscape is emerging to be a key coordinator of mammalian neural regeneration. The roles of two histone 3 lysine 27 (H3K27) demethylases, Kdm6a/b, in controlling neuroprotection and axon regeneration are investigated here. Deleting either Kdm6a or Kdm6b leads to enhanced sensory axon regeneration in the peripheral nervous system (PNS), whereas in the central nervous system (CNS), only deleting Kdm6a in retinal ganglion cells (RGCs) significantly enhances optic nerve regeneration. Moreover, both Kdm6a and Kdm6b function to regulate RGC survival but with different mechanisms. Mechanistically, Kdm6a regulates RGC regeneration via distinct pathway from that of Pten, and co‐deleting Kdm6a and Pten results in long distance optic nerve regeneration passing the optic chiasm. In addition, RNA‐seq profiling reveals that Kdm6a deletion switches the RGC transcriptomics into a developmental‐like state and suppresses several known repressors of neural regeneration. Klf4 is identified as a direct downstream target of Kdm6a‐H3K27me3 signaling in both sensory neurons and RGCs to regulate axon regeneration. These findings not only reveal different roles of Kdm6a and Kdm6b in regulation of neural regeneration and their underlying mechanisms, but also identify Kdm6a‐mediated histone demethylation signaling as a novel epigenetic target for supporting CNS neural regeneration. |
| format | Article |
| id | doaj-art-7c6edb4d94544c11a044c4ab535e1537 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-7c6edb4d94544c11a044c4ab535e15372025-08-20T02:24:50ZengWileyAdvanced Science2198-38442025-04-011216n/an/a10.1002/advs.202405537Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural RegenerationShu‐Guang Yang0Chang‐Ping Li1Xue‐Wei Wang2Tao Huang3Cheng Qian4Qiao Li5Ling‐Rui Zhao6Si‐Yu Zhou7Chen‐Yun Ding8Rui Nie9Saijilafu10Yu‐Cai Hong11Chang‐Mei Liu12Feng‐Quan Zhou13Center for Translational Neural Regeneration Research Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaCenter for Translational Neural Regeneration Research Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaDepartment of Orthopedic Surgery The Johns Hopkins University School of Medicine Baltimore MD 21205 USAState Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD) Department of Cardiovascular Surgery General Hospital of Northern Theater Command Shenyang Liaoning 110016 ChinaDepartment of Orthopedic Surgery The Johns Hopkins University School of Medicine Baltimore MD 21205 USADepartment of Orthopedic Surgery The Johns Hopkins University School of Medicine Baltimore MD 21205 USADepartment of Orthopedic Surgery The Johns Hopkins University School of Medicine Baltimore MD 21205 USACenter for Translational Neural Regeneration Research Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaCenter for Translational Neural Regeneration Research Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaCenter for Translational Neural Regeneration Research Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaKey Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province School of Medicine Hangzhou City University Hangzhou Zhejiang 310015 ChinaDepartment of Emergency Medicine Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaKey Laboratory of Organ Regeneration and Reconstruction Institute of Zoology Chinese Academy of Sciences Institute for Stem Cell and Regeneration Chinese Academy of Sciences Beijing Institute for Stem Cell and Regenerative Medicine Beijing 100101 ChinaCenter for Translational Neural Regeneration Research Sir Run Run Shaw Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310016 ChinaAbstract Epigenetic regulation of neuronal transcriptomic landscape is emerging to be a key coordinator of mammalian neural regeneration. The roles of two histone 3 lysine 27 (H3K27) demethylases, Kdm6a/b, in controlling neuroprotection and axon regeneration are investigated here. Deleting either Kdm6a or Kdm6b leads to enhanced sensory axon regeneration in the peripheral nervous system (PNS), whereas in the central nervous system (CNS), only deleting Kdm6a in retinal ganglion cells (RGCs) significantly enhances optic nerve regeneration. Moreover, both Kdm6a and Kdm6b function to regulate RGC survival but with different mechanisms. Mechanistically, Kdm6a regulates RGC regeneration via distinct pathway from that of Pten, and co‐deleting Kdm6a and Pten results in long distance optic nerve regeneration passing the optic chiasm. In addition, RNA‐seq profiling reveals that Kdm6a deletion switches the RGC transcriptomics into a developmental‐like state and suppresses several known repressors of neural regeneration. Klf4 is identified as a direct downstream target of Kdm6a‐H3K27me3 signaling in both sensory neurons and RGCs to regulate axon regeneration. These findings not only reveal different roles of Kdm6a and Kdm6b in regulation of neural regeneration and their underlying mechanisms, but also identify Kdm6a‐mediated histone demethylation signaling as a novel epigenetic target for supporting CNS neural regeneration.https://doi.org/10.1002/advs.202405537epigenetic regulationhistone methylationKdm6aKdm6bKlf4neuroprotection |
| spellingShingle | Shu‐Guang Yang Chang‐Ping Li Xue‐Wei Wang Tao Huang Cheng Qian Qiao Li Ling‐Rui Zhao Si‐Yu Zhou Chen‐Yun Ding Rui Nie Saijilafu Yu‐Cai Hong Chang‐Mei Liu Feng‐Quan Zhou Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural Regeneration Advanced Science epigenetic regulation histone methylation Kdm6a Kdm6b Klf4 neuroprotection |
| title | Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural Regeneration |
| title_full | Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural Regeneration |
| title_fullStr | Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural Regeneration |
| title_full_unstemmed | Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural Regeneration |
| title_short | Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural Regeneration |
| title_sort | roles of kdm6a and kdm6b in regulation of mammalian neural regeneration |
| topic | epigenetic regulation histone methylation Kdm6a Kdm6b Klf4 neuroprotection |
| url | https://doi.org/10.1002/advs.202405537 |
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