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. The 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.

Epigenetic Mechanisms of Learning and Memory: Implications for Aging

“…This was quickly translated to rodents, where numerous studies show that learning induces histone acetylation [ 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 ] and the manipulation of histone acetylation can alter memory. Specifically, genetic or pharmacological manipulation of HDACs/HATs have generally established that increasing histone acetylation enhances memory, whereas decreasing histone acetylation impairs memory [ 107 , 109 , 111 , 112 , 113 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ].…”

HDAC superfamily promoters acetylation is differentially regulated by modafinil and methamphetamine in the mouse medial prefrontal cortex

“…Among class IIa, HDAC7 is of particular interest given that a single‐dose of modafinil specifically increased H3ac and decreased H4ac at the Hdac7 promoter and increased Hdac7 mRNA levels. HDAC7 seems to play a role in hippocampus‐dependent memory formation and is involved in neuronal protection against apoptotic mechanisms . Interestingly, we and others have shown that modafinil has anti‐oxidative, anti‐inflammatory, and neuroprotective effects on the dopaminergic system .…”

7-Hydroxycoumarin Attenuates Colistin-Induced Kidney Injury in Mice Through the Decreased Level of Histone Deacetylase 1 and the Activation of Nrf2 Signaling Pathway

“…In addition, the expression of Kelch-like ECH-associated protein 1 (Keap1), the negative regulator of Nrf2, was not changed by 7-HC treatment both in control and colistin conditions ( Supplementary Figure 2), which means that 7-HC could activate Nrf2 signaling via Keap1-independent mechanism. Histone acetylation modification, regulated by HDAC, is an important mechanism for gene transcription regulation (Wang et al, 2014;Jing et al, 2017). Increasing evidences have emphasized the importance of HDAC-regulated epigenetic modification in the development of kidney injury (Wang et al, 2014;Ma et al, 2017;Yoshikazu et al, 2018).…”

“…Histone acetylation modification, regulated by HDAC, is an important mechanism for gene transcription regulation ( Wang et al, 2014 ; Jing et al, 2017 ). Increasing evidences have emphasized the importance of HDAC-regulated epigenetic modification in the development of kidney injury ( Wang et al, 2014 ; Ma et al, 2017 ; Yoshikazu et al, 2018 ).…”