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.
Highlights
Histone acetylation is an important epigenetic mechanism for transcriptional control and its levels are regulated by the activities of histone acetyltransferases (HATs) and deacetylases (HDACs)
Histone acetylation levels are reduced in cortical neurons after injurious ischemia To investigate whether acetylation of histones in neurons is affected by ischemia, we exploited an established in vitro model of ischemic cell death
A slight induction of gelsolin mRNA was observed in control cultures, significant upregulation was detected in cultures that underwent ischemic preconditioning. These results suggest that CREB-binding protein (CBP) and histone acetylation are likely parts of neuroprotective mechanisms that are induced by ischemic preconditioning in neurons
Summary
Histone acetylation is an important epigenetic mechanism for transcriptional control and its levels are regulated by the activities of histone acetyltransferases (HATs) and deacetylases (HDACs). HDAC inhibitors have been used consistently and successfully in an array of neurological disease models including poly-glutamine toxicity, spinal muscular atrophy, intracerebral hemorrhage and cerebral ischemia [5,6,7,8,9,10,11]. CBP is a transcriptional co-activator with HAT activity that was shown to be important for long-term memory processes, which depend on de novo gene expression [12,13,14]. In contrast to several chronic neurodegenerative disease models [16,17,18,19], the role of CBP and histone acetylation in acute neurological diseases like cerebral ischemia are poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
