Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity

doi:10.1038/s41380-019-0533-y

	Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity
	Chen, Zhong-Guo 1,4,5; Wang, Yu-Jun 4; Chen, Ruo-Song 2,4; Geng, Fan 5; Gan, Chen-Ling 1; Wang, Wei-Sheng 4; Liu, Xing 4; Zhou, Hu 4; He, Ling 1; Hu, Gang 5
刊名	MOLECULAR PSYCHIATRY
	2021-04-01
卷号	26 期号:4 页码:1162-1177
ISSN号	1359-4184
DOI	10.1038/s41380-019-0533-y
通讯作者	Hu, Gang(ghu@njmu.edu.cn) ; Liu, Jing-Gen(jgliu@simm.ac.cn)
英文摘要	Compelling evidence suggests that synaptic structural plasticity, driven by remodeling of the actin cytoskeleton, underlies addictive drugs-induced long-lasting behavioral plasticity. However, the signaling mechanisms leading to actin cytoskeleton remodeling remain poorly defined. DNA methylation is a critical mechanism used to control activity-dependent gene expression essential for long-lasting synaptic plasticity. Here, we provide evidence that DNA methyltransferase DNMT3a is degraded by the E2 ubiquitin-conjugating enzyme Ube2b-mediated ubiquitination in dorsal hippocampus (DH) of rats that repeatedly self-administrated heroin. DNMT3a degradation leads to demethylation in CaMKK1 gene promotor, thereby facilitating CaMKK1 expression and consequent activation of its downstream target CaMKI alpha, an essential regulator of spinogenesis. CaMKK1/CaMKI alpha signaling regulates actin cytoskeleton remodeling in the DH and behavioral plasticity by activation of Rac1 via acting Rac guanine-nucleotide-exchange factor beta PIX. These data suggest that Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on CaMKK1 gene and thus activates CaMKK1/CaMKI alpha/beta PIX/Rac1 cascade, leading to drug use-induced actin polymerization and behavior plasticity.
资助项目	China Postdoctoral Science Foundation[2015M570392] ; National Natural Science Foundation of China (National Science Foundation of China)[81130087] ; National Natural Science Foundation of China (National Science Foundation of China)[81773710] ; National Natural Science Foundation of China (National Science Foundation of China)[81671322] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences (Youth Innovation Promotion Association CAS)[2017334]
WOS研究方向	Biochemistry & Molecular Biology ; Neurosciences & Neurology ; Psychiatry
语种	英语
出版者	SPRINGERNATURE
WOS记录号	WOS:000632144900010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295403]
专题	中国科学院上海药物研究所
通讯作者	Hu, Gang; Liu, Jing-Gen
作者单位	1.China Pharmaceut Univ, Dept Pharmacol, Nanjing 210008, Peoples R China 2.Univ Chinese Acad Sci, Shanghai 200031, Peoples R China 3.Zhejiang Chinese Med Univ, Clin Med Coll 3, Dept Neurobiol & Acupuncture, Key Lab Acupuncture & Neurobiol Zhejiang Prov, Hangzhou 310053, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China 5.Nanjing Med Univ, Dept Pharmacol, Nanjing 211166, Peoples R China
推荐引用方式 GB/T 7714	Chen, Zhong-Guo,Wang, Yu-Jun,Chen, Ruo-Song,et al. Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity[J]. MOLECULAR PSYCHIATRY,2021,26(4):1162-1177.
APA	Chen, Zhong-Guo.,Wang, Yu-Jun.,Chen, Ruo-Song.,Geng, Fan.,Gan, Chen-Ling.,...&Liu, Jing-Gen.(2021).Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity.MOLECULAR PSYCHIATRY,26(4),1162-1177.
MLA	Chen, Zhong-Guo,et al."Ube2b-dependent degradation of DNMT3a relieves a transcriptional brake on opiate-induced synaptic and behavioral plasticity".MOLECULAR PSYCHIATRY 26.4(2021):1162-1177.