title: HDAC7 Ubiquitination by the E3 Ligase CBX4 Is Involved in Contextual Fear Conditioning Memory Formation.
abstract: Histone acetylation, an epigenetic modification, plays an important role in long-term memory formation. Recently, histone deacetylase (HDAC) inhibitors were demonstrated to promote memory formation, which raises the intriguing possibility that they may be used to rescue memory deficits. However, additional research is necessary to clarify the roles of individual HDACs in memory. In this study, we demonstrated that HDAC7, within the dorsal hippocampus of C57BL6J mice, had a late and persistent decrease after contextual fear conditioning (CFC) training (4-24 h), which was involved in long-term CFC memory formation. We also showed that HDAC7 decreased via ubiquitin-dependent degradation. CBX4 was one of the HDAC7 E3 ligases involved in this process. Nur77, as one of the target genes of HDAC7, increased 6-24 h after CFC training and, accordingly, modulated the formation of CFC memory. Finally, HDAC7 was involved in the formation of other hippocampal-dependent memories, including the Morris water maze and object location test. The current findings facilitate an understanding of the molecular and cellular mechanisms of HDAC7 in the regulation of hippocampal-dependent memory.SIGNIFICANCE STATEMENTThe current findings demonstrated the effects of histone deacetylase 7 (HDAC7) on hippocampal-dependent memories. Moreover, we determined the mechanism of decreased HDAC7 in contextual fear conditioning (CFC) through ubiquitin-dependent protein degradation. We also verified that CBX4 was one of the HDAC7 E3 ligases. Finally, we demonstrated that Nur77, as one of the important targets for HDAC7, was involved in CFC memory formation. All of these proteins, including HDAC7, CBX4, and Nur77, could be potential therapeutic targets for preventing memory deficits in aging and neurological diseases.
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Xu
authors.identifier: 0000-0003-4864-1870
authors.initials: X
authors.lastname: Jing
authors.affiliation: The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China, and.
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Sui
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Xu
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Yuan
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Hui-Xian
authors.initials: HX
authors.lastname: Ma
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Ying-Xiao
authors.initials: YX
authors.lastname: Zhu
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Jin-Kai
authors.initials: JK
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yi
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China.
authors.forename: Zhe-Yu
authors.initials: ZY
authors.lastname: Chen
authors.affiliation: Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China, wangyue@sdu.edu.cn.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological / Q000502:physiology; D005239:Fear / Q000502:physiology* / Q000523:psychology; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008025:Ligases / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases; D008025:Ligases; C570504:Cbx4 protein, mouse
keywords: CBX4; CFC; HDAC7; Nur77; ubiquitination