Epigenetic Mechanisms in Cerebral Ischemia

Abstract

Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration.

Effects of Different Modes of Hypobaric Hypoxia on the Content of Epigenetic Factors in the Rat in Neurons of Rat Neocortex

“…The increase in acH3K24 content detected after 3 sessions of MHH promoted the formation of euchromatin and facilitates the delivery of transcription factors (CREB, Hif, NF-κB, c-Fos, etc.) to target gene promoters [5,11,14]. The increase in meH3K9 content caused by SHH and single MHH promoted chromatin condensation (formation of heterochromatin) and reduced accessibility of target genes for transcription factors [5,12,15].…”

“…Acetylation, methylation, phosphorylation, and ubiquitination of histones largely determine the access of transcription factors to the target genes [3,5,13,14]. DNA methylation leads to gene repression [11]. The role of epigenetic mechanisms regulating activities of various genes in cell reactions to hypoxia has been in the focus of recent research.…”

“…Despite numerous studies, the genome-dependent mechanisms of formation of neuronal reactions to hypoxia, inducing pathological or adaptive conditions of the brain, remain not quite clear [1]. Severe forms of hypoxia cause mainly reduction of gene transcription [4,5,11]. On the other hand, we have shown that moderate hypobaric hypoxia used in the preconditioning mode is characterized by a neuroprotective effect, if used according to certain protocols, and induces the expression of some proadaptive genes and their products [1].…”

Interplay between histone acetylation/deacetylation and poly(ADP-ribosyl)ation in the development of ischemic tolerance in vitro

“…Numerous studies have demonstrated that in experimental models of cerebral ischemia in vivo there is an imbalance in the acetylation/deacetylation homeostasis that can be prevented by using HDAC inhibitors that restore histone acetylation levels (see for reviews: (Langley et al, 2009;Gibson and Murphy, 2010;Schweizer et al, 2013). Along this line, we have previously demonstrated that in the ischemic brain tissue of rats subjected to middle cerebral artery occlusion for 6 h, histone H3 acetylation levels were drastically reduced, with no evidence for a concomitant change of histone acetyl-transferase or deacetylase activities, and that treatment with the HDAC inhibitor SAHA increased histone acetylation in the normal brain and prevented deacetylation in the ischemic brain (Faraco et al, 2006).…”

“…A number of studies (reviewed in: Langley et al, 2009;Gibson and Murphy, 2010;Schweizer et al, 2013) have shown that histone acetylation is reduced following cerebral ischemia and that class I, II and IV HDAC inhibitors are able to ameliorate neuronal death and cognitive deficits following transient (Endres et al, 2000;Ren et al, 2004;Qi et al, 2004;Faraco et al, 2006;Yildrim et al, 2008;Wang et al, 2012) and permanent Langley et al, 2008;Kim et al, 2009) focal ischemia and in a model of transient global ischemia (Xuan et al, 2012). These effects appear to be due to the maintenance of histone acetylation levels, the expression of cell survival (Bcl-2, Bcl-XL, Hsp70) and regenerative (BDNF) pathways, and the downregulation of pro-inflammatory genes (COX-2, iNOS, TNF-a, IL-b) (Faraco et al, 2006;Kim et al, 2007Kim et al, , 2009.…”