title: Loss of GCN5 leads to increased neuronal apoptosis by upregulating E2F1- and Egr-1-dependent BH3-only protein Bim.
abstract: Cellular acetylation homeostasis is a kinetic balance precisely controlled by histone acetyl-transferase (HAT) and histone deacetylase (HDAC) activities. The loss of the counterbalancing function of basal HAT activity alters the precious HAT:HDAC balance towards enhanced histone deacetylation, resulting in a loss of acetylation homeostasis, which is closely associated with neuronal apoptosis. However, the critical HAT member whose activity loss contributes to neuronal apoptosis remains to be identified. In this study, we found that inactivation of GCN5 by either pharmacological inhibitors, such as CPTH2 and MB-3, or by inactivation with siRNAs leads to a typical apoptosis in cultured cerebellar granule neurons. Mechanistically, the BH3-only protein Bim is transcriptionally upregulated by activated Egr-1 and E2F1 and mediates apoptosis following GCN5 inhibition. Furthermore, in the activity withdrawal- or glutamate-evoked neuronal apoptosis models, GCN5 loses its activity, in contrast to Bim induction. Adenovirus-mediated overexpression of GCN5 suppresses Bim induction and apoptosis. Interestingly, the loss of GCN5 activity and the induction of Egr-1, E2F1 and Bim are involved in the early brain injury (EBI) following subarachnoid haemorrhage (SAH) in rats. HDAC inhibition not only significantly rescues Bim expression and apoptosis induced by either potassium deprivation or GCN5 inactivation but also ameliorates these events and EBI in SAH rats. Taken together, our results highlight a new mechanism by which the loss of GCN5 activity promotes neuronal apoptosis through the transcriptional upregulation of Bim, which is probably a critical event in triggering neuronal death when cellular acetylation homeostasis is impaired.
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Guangdong Province Key laboratory of Brain Function and Disease, Guangzhou 510006, China.|Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.
authors.forename: Yangpeng
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.
authors.forename: Shiyin
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.
authors.forename: Sidian
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of General Dentistry, 323 Hospital of the People's Liberation Army, Xi'an, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.
authors.forename: Longchang
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Radiology, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, the Second Affiliated Hospital and Institute of Neurosciences of Guangzhou Medical University, Guangzhou 510260, China.|Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou 510260, China.|Guangdong Province Key laboratory of Brain Function and Disease, Guangzhou 510006, China.
authors.forename: Zhongmin
authors.identifier: 0000-0002-2395-673X
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000494:pharmacology; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000187:drug effects; D000099224:p300-CBP-Associated Factor
chemical_list: D000072224:Bcl-2-Like Protein 11; D050687:E2F1 Transcription Factor; D051766:Early Growth Response Protein 1; D018698:Glutamic Acid; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases; D011188:Potassium; D034741:RNA, Small Interfering; C556665:Kat2a protein, rat; D000099224:p300-CBP-Associated Factor