Polycomb group proteins as epigenetic mediators of neuroprotection in ischemic tolerance.
ABSTRACT Exposing the brain to sublethal ischemia affects the response to a subsequent, otherwise injurious ischemia, resulting in transcriptional suppression and neuroprotection, a response called ischemic tolerance. Here, we show that the proteomic signature of the ischemic-tolerant brain is characterized by increased abundance of transcriptional repressors, particularly polycomb group (PcG) proteins. Knocking down PcG proteins precluded the induction of ischemic tolerance, whereas in an in vitro model, overexpressing the PcG proteins SCMH1 or BMI1 induced tolerance to ischemia without preconditioning. We found that PcG proteins are associated with the promoter regions of genes encoding two potassium channel proteins that show decreased abundance in ischemic-tolerant brains. Furthermore, PcG proteins decreased potassium currents in cultured neuronal cells, and knocking down potassium channels elicited tolerance without preconditioning. These findings reveal a previously unknown mechanism of neuroprotection that involves gene repressors of the PcG family.
SourceAvailable from: James Peter Reynolds[Show abstract] [Hide abstract]
ABSTRACT: Exposure of the brain to brief, non-harmful seizures can activate protective mechanisms that temporarily generate a damage-refractory state. This process, termed epileptic tolerance, is associated with large-scale down-regulation of gene expression. Polycomb group proteins are master controllers of gene silencing during development that are re-activated by injury to the brain. Here we explored the transcriptional response of genes associated with polycomb repressor complex (PRC) 1 (Ring1A and Ring1B and Bmi1) and PRC2 (Ezh1, Ezh2 and Suz12), as well as additional transcriptional regulators Sirt1, Yy1 and Yy2, in a mouse model of status epilepticus. Findings were contrasted to changes after status epilepticus in mice previously given brief seizures to evoke tolerance. Real-time quantitative PCR showed status epilepticus prompted an early (1 h) increase in expression of several genes in PRC1 and PRC2 in the hippocampus, followed by down-regulation of many of the same genes at later times points (4 , 8 and 24 h). Spatio-temporal differences were found among PRC2 genes in epileptic tolerance, including increased expression of Ezh2, Suz12 and Yy2 relative to the normal injury response to status epilepticus. In contrast, PRC1 complex genes including Ring 1B and Bmi1 displayed differential down-regulation in epileptic tolerance. The present study characterizes polycomb group gene expression following status epilepticus and shows prior seizure exposure produces select changes to PRC1 and PRC2 composition that may influence differential gene expression in epileptic tolerance.Frontiers in Neurology 02/2015; 6. DOI:10.3389/fneur.2015.00046
[Show abstract] [Hide abstract]
ABSTRACT: Significant reductions in the extent of acute injury in the CNS can be achieved by exposure to different preconditioning stimuli, but the duration of the induced protective phenotype is typically short-lasting, and thus is deemed as limiting its clinical applicability. Extending the period over which such adaptive epigenetic changes persist - in effect, expanding conditioning's "therapeutic window" - would significantly broaden the potential applications of such a treatment approach in patients. The frequency of the conditioning stimulus may hold the key. While transient (1-3 days) protection against CNS ischemic injury is well established preclinically following a single preconditioning stimulus, repetitively presenting preconditioning stimuli extends the duration of ischemic tolerance by many weeks. Moreover, repetitive intermittent postconditioning enhances post-ischemic recovery metrics and improves long-term survival. Intermittent conditioning is also efficacious for preventing or delaying injury in preclinical models of chronic neurodegenerative disease, and for promoting long-lasting functional improvements in a number of other pathologies as well. Although the detailed mechanisms underlying these protracted kinds of neuroplasticity remain largely unstudied, accumulating empirical evidence supports the contention that all of these adaptive phenotypes are epigenetically mediated. Going forward, additional preclinical demonstrations of the ability to induce sustained beneficial phenotypes that reduce the burden of acute and chronic neurodegeneration, and experimental interrogations of the regulatory constructs responsible for these epigenetic responses, will accelerate the identification of not only efficacious but also practical, adaptive epigenetics-based treatments for individuals with neurological disease.Frontiers in Neurology 03/2015; 6:42. DOI:10.3389/fneur.2015.00042
[Show abstract] [Hide abstract]
ABSTRACT: Endogenous mechanisms of protection against ischemia can be demonstrated in brain and other organs. The induction of such protection is via a response to sub lethal stress which induces "preconditioning". The preconditioned organ is then "tolerant" to injury from subsequent severe stress of the same or different etiology. Protection is substantial (70% reduction) but delayed in onset and is transient. Gene expression is unique between brains preconditioned, injured (stroke) or made tolerant. Thus, preconditioning reprograms the response to lethal ischemic stress (stroke), reprogrammed from an injury induction response to a neuroprotective processes. Postconditioning refers to attenuation of injurious processes occurring during reperfusion of ischemic brain. Transient mechanical interruption of reperfusion induces post-conditioning which can attenuate reperfusion injury. Post-conditioning protects ischemic brain by decreasing reperfusion induced oxygen free radical formation. The free radicals produce injury via mitochondrial damage which can be repaired experimentally. Post-conditioning produces neuroprotection as potent as experimental preconditioning. The recognition of broad based gene silencing (suppression of thousands of genes) as the phenotype of the preconditioned, ischemic tolerant brain, may explain failure of all single target drugs for stroke. As risks of reperfusion injury accompany treatment for acute stroke, endogenous neuroprotective and repair mechanisms offer translational stroke therapy.Dose-Response 12/2014; 12(4):590-9. DOI:10.2203/dose-response.14-026.Simon · 1.23 Impact Factor