An epigenetic memory at the gene in cancer-resistant, pollution-adapted killifish.

Human exposure to polycyclic aromatic hydrocarbons (PAH) is a significant and growing public health problem. Frequent, high dose exposures are likely to increase due to a warming climate and increased frequency of large-scale wildfires. Here, we characterize an epigenetic memory at the () gene in a population of wild that has adapted to chronic, extreme PAH pollution. In wild-type fish, is highly induced by PAH. In PAH-tolerant fish, induction is blunted. Since CYP1A metabolically activates PAH, this memory protects these fish from PAH-mediated cancer. However, PAH-tolerant fish reared in clean water recover inducibility, indicating that blunted induction is a non-genetic memory of prior exposure. To explore this possibility, we bred depurated wild fish from PAH-sensitive and - tolerant populations, manually fertilized exposure-naïve embryos, and challenged them with PAH. We observed epigenetic control of the reversible memory of generational PAH stress in F PAH-tolerant embryos. Specifically, we observed a bivalent domain in the promoter enhancer comprising both activating and repressive histone post-translational modifications. Activating modifications, relative to repressive ones, showed greater increases in response to PAH in sensitive embryos, relative to tolerant, consistent with greater gene activation. Also, PAH-tolerant adult fish showed persistent induction of long after exposure cessation, which is consistent with defective shutoff and recovery to baseline. Since expression is inversely correlated with cancer risk, these results indicate that PAH-tolerant fish have epigenetic protection against PAH-induced cancer in early life that degrades in response to continuous gene activation.