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Epigenetics and the Environment: In Search of the “Toleroasome” Vital to Execution of Ischemic Preconditioning

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Abstract

Activation and repression of gene expression are key features of ischemic tolerance. Converging lines of inquiry from several groups suggests that epigenetic proteins may transduce sublethal stresses, including bioenergetic or oxidative stress into durable (2–3 days) changes in gene expression that mediate ischemic tolerance. Here we discuss the potential mechanisms by which changes in cell state (e.g., ATP, NAD+, and oxygen) can modify specific targets including polycomb complexes, jumonji domain histone demethylases, and zinc and NAD-dependent histone decetylases and thus trigger an adaptive program. A major unanswered question is whether these proteins work in parallel or convergently as part of a “tolerosome” (tolero is the Latin word for tolerance), a multiprotein complex recruited to promoters or enhancers of specific genes, to mediate preconditioning. Whatever the case may be, epigenetic proteins are fertile targets for the treatment of stroke.

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Acknowledgments

We would like to thank Dr. Miguel Perez-Pinzon and his colleagues for organizing a very interactive and fruitful meeting on the clinical and scientific aspects of ischemic preconditioning. We would also like to thank members of the Ratan Lab, particularly Sama Sleiman, Manuela Basso, Saravanan Karuppagounder, Hossein Aleyasin, and Thong Ma for helpful discussions that shaped the ideas presented here. We also acknowledge generous support from the NIA (P01 AG14930-10), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Dana Foundation.

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Correspondence to Rajiv R. Ratan.

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Review for proceedings from Meeting on Ischemic Preconditioning, December 8th, University of Miami.

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Brand, D., Ratan, R.R. Epigenetics and the Environment: In Search of the “Toleroasome” Vital to Execution of Ischemic Preconditioning. Transl. Stroke Res. 4, 56–62 (2013). https://doi.org/10.1007/s12975-012-0235-0

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