title: Histone acetylation and CREB binding protein are required for neuronal resistance against ischemic injury.
abstract: Epigenetic transcriptional regulation by histone acetylation depends on the balance between histone acetyltransferase (HAT) and deacetylase activities (HDAC). Inhibition of HDAC activity provides neuroprotection, indicating that the outcome of cerebral ischemia depends crucially on the acetylation status of histones. In the present study, we characterized the changes in histone acetylation levels in ischemia models of focal cerebral ischemia and identified cAMP-response element binding protein (CREB)-binding protein (CBP) as a crucial factor in the susceptibility of neurons to ischemic stress. Both neuron-specific RNA interference and neurons derived from CBP heterozygous knockout mice showed increased damage after oxygen-glucose deprivation (OGD) in vitro. Furthermore, we demonstrated that ischemic preconditioning by a short (5 min) subthreshold occlusion of the middle cerebral artery (MCA), followed 24 h afterwards by a 30 min occlusion of the MCA, increased histone acetylation levels in vivo. Ischemic preconditioning enhanced CBP recruitment and histone acetylation at the promoter of the neuroprotective gene gelsolin leading to increased gelsolin expression in neurons. Inhibition of CBP's HAT activity attenuated neuronal ischemic preconditioning. Taken together, our findings suggest that the levels of CBP and histone acetylation determine stroke outcome and are crucially associated with the induction of an ischemia-resistant state in neurons.
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ferah
authors.initials: F
authors.lastname: Yildirim
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Shengbo
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany; Klinik und Poliklinik für Psychiatrie, Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Golo
authors.initials: G
authors.lastname: Kronenberg
authors.affiliation: Instituto de Neurociencias de Alicante (Universidad Miguel Hernandez-Consejo Superior de Investigaciones Cientificas), Campus de Sant Joan, Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Barco
authors.affiliation: Instituto de Neurociencias de Alicante (Universidad Miguel Hernandez-Consejo Superior de Investigaciones Cientificas), Campus de Sant Joan, Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Roman
authors.initials: R
authors.lastname: Olivares
authors.affiliation: Instituto de Neurociencias de Alicante (Universidad Miguel Hernandez-Consejo Superior de Investigaciones Cientificas), Campus de Sant Joan, Sant Joan d'Alacant, Alicante, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Benito
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany; ExcellenceCluster NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany; ExcellenceCluster NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Gertz
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany; ExcellenceCluster NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Endres
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Harms
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB) and Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany; ExcellenceCluster NeuroCure, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meisel
mesh_terms: D000107:Acetylation; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology; D004195:Disease Models, Animal; D018260:Gelsolin / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D006657:Histones / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic
chemical_list: D018260:Gelsolin; D006657:Histones; D050882:CREB-Binding Protein; D003474:Curcumin
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