Roles of Kdm6a and Kdm6b in Regulation of Mammalian Neural Regeneration

被引：2

作者：

Yang, Shu-Guang ^{[1
,2
]}

Li, Chang-Ping ^{[1
,3
,4
]}

Wang, Xue-Wei ^{[2
,5
,6
,7
]}

Huang, Tao ^{[8
]}

Qian, Cheng ^{[2
]}

Li, Qiao ^{[2
]}

Zhao, Ling-Rui ^{[2
]}

Zhou, Si-Yu ^{[1
]}

Ding, Chen-Yun ^{[1
]}

Nie, Rui ^{[1
]}

Saijilafu ^{[9
]}

Hong, Yu-Cai ^{[10
]}

Liu, Chang-Mei ^{[3
,4
]}

Zhou, Feng-Quan ^{[1
,2
,11
]}

机构：

[1] Zhejiang Univ, Sir Run Run Shaw Hosp, Sch Med, Ctr Translat Neural Regenerat Res, Hangzhou 310016, Zhejiang, Peoples R China

[2] Johns Hopkins Univ, Sch Med, Dept Orthoped Surg, Baltimore, MD 21205 USA

[3] Chinese Acad Sci, Beijing Inst Stem Cell & Regenerat Med, Inst Stem Cell & Regenerat, Inst Zool,Key Lab Organ Regenerat & Reconstruct, Beijing 100101, Peoples R China

[4] Univ Chinese Acad Sci, Savaid Med Sch, Beijing 100049, Peoples R China

[5] Univ S Florida, Byrd Alzheimers Ctr, Tampa, FL 33613 USA

[6] Univ S Florida, Res Inst, Tampa, FL 33613 USA

[7] Univ S Florida, Dept Mol Med, Morsani Coll Med, Tampa, FL 33612 USA

[8] Gen Hosp Northern Theater Command, Dept Cardiovasc Surg, State Key Lab Frigid Zone Cardiovasc Dis SKLFZCD, Shenyang 110016, Liaoning, Peoples R China

[9] Hangzhou City Univ, Sch Med, Key Lab Novel Targets & Drug Study Neural Repair, Hangzhou 310015, Zhejiang, Peoples R China

[10] Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Emergency Med, Hangzhou 310016, Zhejiang, Peoples R China

[11] Johns Hopkins Univ, Sch Med, Solomon H Dept Neurosci, Baltimore, MD 21205 USA

来源：

ADVANCED SCIENCE | 2025年 / 12卷 / 16期

基金：

美国国家科学基金会;

关键词：

epigenetic regulation; histone methylation; Kdm6a; Kdm6b; Klf4; neuroprotection; optic nerve regeneration; sensory axon regeneration; PROMOTES AXON REGENERATION; H3K27ME3 DEMETHYLASE UTX; TUMOR-SUPPRESSOR; OPTIC-NERVE; JMJD3; DIFFERENTIATION; DELETION; INJURY; MODULATION; EXPRESSION;

D O I：

10.1002/advs.202405537

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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.

引用

页数：23

共 91 条

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