Epigenetics and the Environment: In Search of the "Toleroasome" Vital to Execution of Ischemic Preconditioning
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.