Cdyl Deficiency Brakes Neuronal Excitability and Nociception through Promoting Kcnb1 Transcription in Peripheral Sensory Neurons.
Cdyl Deficiency Brakes Neuronal Excitability and Nociception through Promoting Kcnb1 Transcription in Peripheral Sensory Neurons.
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DOI：
10.1002/advs.202104317
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发表时间：
2022-04
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Sun ZW;Waybright JM;Beldar S;Chen L;Foley CA;Norris-Drouin JL;Lyu TJ;Dong A;Min J;Wang YP;James LI;Wang Y
表观遗传修饰参与疼痛的发生、发展和维持；然而，疼痛调节的精确表观遗传机制仍然难以捉摸。本文报道表观遗传因子Y -样色域（CDYL）在疼痛加工中起着至关重要的作用。选择性敲除感觉神经元中的CDYL可导致神经元兴奋性和伤害性降低。此外，CDYL促进组蛋白3赖氨酸27三甲基化（H3K27me3）沉积在Kcnb1内含子区域，从而沉默电压门控钾通道（Kv）亚家族成员Kv2.1的转录。CDYL缺失功能增强背根神经节总Kv和Kv2.1电流密度，Kv2.1敲低逆转CDYL缺失小鼠的疼痛相关表型。此外，局灶性给药一种新型的强效CDYL拮抗剂可以减弱伤害感觉并减轻神经性疼痛。这些发现表明，CDYL是疼痛感觉的关键调节因子，并为开发针对表观遗传机制的新型镇痛药提供了线索。外周感觉神经元中的Y样色域（CDYL）在疼痛感觉中是不可或缺的。外周CDYL下调，神经元兴奋性降低，痛阈升高。其中一个关键机制是CDYL的缺失抑制了组蛋白3赖氨酸27三甲基化（H3K27me3）在Kcnb1内含子区域的沉积，并促进了其转录。更重要的是，一种新型CDYL拮抗剂的局灶递送成功地减轻了神经性疼痛，为临床转化提供了可能性。
Epigenetic modifications are involved in the onset, development, and maintenance of pain; however, the precise epigenetic mechanism underlying pain regulation remains elusive. Here it is reported that the epigenetic factor chromodomain Y‐like (CDYL) is crucial for pain processing. Selective knockout of CDYL in sensory neurons results in decreased neuronal excitability and nociception. Moreover, CDYL facilitates histone 3 lysine 27 trimethylation (H3K27me3) deposition at the Kcnb1 intron region thus silencing voltage‐gated potassium channel (Kv) subfamily member Kv2.1 transcription. Loss function of CDYL enhances total Kv and Kv2.1 current density in dorsal root ganglia and knockdown of Kv2.1 reverses the pain‐related phenotypes of Cdyl deficiency mice. Furthermore, focal administration of a novel potent CDYL antagonist blunts nociception and attenuates neuropathic pain. These findings reveal that CDYL is a critical regulator of pain sensation and shed light on the development of novel analgesics targeting epigenetic mechanisms. Chromodomain Y‐like (CDYL) in peripheral sensory neurons is indispensable for pain sensation. Downregulation of peripheral CDYL decreases neuronal excitability and elevates pain threshold. One of the critical mechanisms is that loss of CDYL represses histone 3 lysine 27 trimethylation (H3K27me3) deposition at Kcnb1 intron region and facilitates its transcription. More importantly, focal delivery of a novel CDYL antagonist successfully attenuates neuropathic pain, providing probability for clinical translation.
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影响因子：
64.5
作者：
Duan B;Cheng L;Bourane S;Britz O;Padilla C;Garcia-Campmany L;Krashes M;Knowlton W;Velasquez T;Ren X;Ross S;Lowell BB;Wang Y;Goulding M;Ma Q
通讯作者：
Ma Q
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.4
作者：
Liu, Lian;Xu, Dan;Tang, Yuying
通讯作者：
Tang, Yuying
影响因子：
16.6
作者：
Chen, Chao;Zhang, Jinhui;Yang, Guang
通讯作者：
Yang, Guang
CDYL 通过抑制轴突 Nav1.6 钠通道表达来抑制小鼠癫痫发生。
影响因子：
16.6
作者：
Liu Y;Lai S;Ma W;Ke W;Zhang C;Liu S;Zhang Y;Pei F;Li S;Yi M;Shu Y;Shang Y;Liang J;Huang Z
通讯作者：
Huang Z