Polycomb Group Proteins as Epigenetic Mediators of Neuroprotection in Ischemic Tolerance
Waters Corporation, Milford, MA 01757, USA. Science Signaling
(Impact Factor: 6.28).
03/2010; 3(111):ra15. DOI: 10.1126/scisignal.2000502
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.
Available from: dos.sagepub.com
- "Although transcriptional suppression characterizes tolerant brain, the protection is protein synthesis dependent. Up regulation of polycomb group proteins have been found as tolerance effectors in brain ischemia and to act as transcriptional suppressors via epigenetic mechanisms (Stapels et al., 2010). Retrospective data support a clinical counterpart of preconditioning in human brain: patients with prodromal transient ischemic attacks (TIA) have milder strokes(Weih et al., 1999). "
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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.
Available from: Maria-Grazia De Simoni
- "Our findings seem to be in agreement with this, showing decreased relative abundance of proteins involved in different processes , and in particular energy metabolism. At variance with our data, Stapels et al. 2010 did not find expression changes of the proteins we found to be down-regulated in the ischemic-tolerant brain, rather they reported increased abundance of transcriptional repressors such as proteins of the polycomb group, suggesting that neuroprotection is induced by transcriptional repression (Stapels et al. 2010). We have not been able to identify any polycomb group protein, either because of the lower sensitivity of our proteomic approach or because in this study, the IPC-induced tolerant proteome was investigated at longer time points. "
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ABSTRACT: J. Neurochem. (2012) 122, 1219–1229.
The molecular mechanisms that lead to ischemic pre-conditioning are not completely understood, and proteins are important players. We compared the mouse brain cortex proteome from different ischemia sets: transient (7 min) middle cerebral artery occlusion (7′MCAo, pre-conditioning stimulus), permanent MCAo (pMCAo, severe ischemia), and pMCAo 4 days after 7′MCAo (7′MCAo/pMCAo, pre-conditioned model). Proteins were analyzed by two-dimensional electrophoresis coupled to liquid chromatography–tandem mass spectrometry. Overall, 28 proteins were expressed differentially from sham controls, and identified. The ischemic pre-conditioning stimulus alone up-regulated the stress protein heat-shock protein 70 (HSP70), possibly activated by the androgen receptor. Western blotting confirmed the increased expression of HSP70 and showed that androgen receptor expression paralleled that of HSP70. In the ischemic-tolerant group (7′MCAo/pMCAo), a number of proteins over-expressed after pMCAo returned to sham levels, seven proteins remained up-regulated as in pMCAo, and five proteins mainly involved in energy metabolism and mitochondrial electron transport and unchanged in pMCAo were down-regulated only in ischemic tolerance, suggesting a role in brain pre-conditioning. Astrocytes participated in ischemic-tolerance induction, as shown by the down-regulation of glutamine synthetase in the 7′MCAo/pMCAo group. The results suggest that metabolic down-regulation was a general feature of ischemic pre-conditioning, playing a pivotal role in neuroprotection.
Available from: Hiromitsu Nakauchi
- "Of note, the effect of Bmi1 overexpression in serial transplantation resembles that of overexpression of Ezh2, a gene encoding a core component of PRC2 . Overexpression of PcG genes, Bmi1 and Scmh1, also induces tolerance of cortical neurons to ischemia . Thus, various cellular stresses may target PcG complexes to release transcriptional repression of PcG-regulated genes, such as tumor suppressor and developmental regulator genes, thereby affecting stemness. "
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ABSTRACT: The polycomb-group (PcG) proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of Bmi1, a gene encoding a core component of polycomb repressive complex (PRC) 1, maintained self-renewing hematopoietic stem cells (HSCs) during long-term culture. However, the effects of overexpression of Bmi1 on HSCs in vivo remained to be precisely addressed.
In this study, we generated a mouse line where Bmi1 can be conditionally overexpressed under the control of the endogenous Rosa26 promoter in a hematopoietic cell-specific fashion (Tie2-Cre;R26Stop(FL)Bmi1). Although overexpression of Bmi1 did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during ex vivo culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of Bmi1 had no effect on DNA damage response triggered by ionizing radiation. In contrast, Tie2-Cre;R26Stop(FL)Bmi1 HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of Bmi1 had no impact on the level of intracellular reactive oxygen species (ROS).
Our findings demonstrate that overexpression of Bmi1 confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it.
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