An epigenetic memory at theCYP1Agene in cancer-resistant, pollution-adapted killifish

Abstract

AbstractHuman 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 thecytochrome P450 1A(CYP1A) gene in a population of wildFundulus heteroclitusthat has adapted to chronic, extreme PAH pollution. In wild-type fish,CYP1Ais highly induced by PAH. In PAH-tolerant fish,CYP1Ainduction is blunted. Since CYP1A metabolically activates PAH, this memory protects these fish from PAH-mediated cancer. However, PAH-tolerant fish reared in clean water recoverCYP1Ainducibility, 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 F1PAH-tolerant embryos. Specifically, we observed a bivalent domain in theCYP1Apromoter 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 ofCYP1Along after exposure cessation, which is consistent with defectiveCYP1Ashutoff and recovery to baseline. SinceCYP1Aexpression 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.SignificanceEpigenetic memory, or the inheritance across cell division within an organism or across generations, of environmental exposure response is a compelling phenomenon with limited understanding of mechanism. Here, we characterized an epigenetic memory at theCYP1Agene in pollution-adaptedFundulus heteroclitus. We found that theCYP1Apromoter enhancer contains a bivalent domain, comprising both active and repressive histone modifications, that shows reduced function correlating with reduced gene induction by its pollutant activator. In early life, this memory protects fish against pollution-induced cancer. However, this reduced function carries a cost; adult fish show defective transcriptional recovery ofCYP1A, which increases cancer risk later in life. These results provide an initial mechanism for a model epigenetic memory and highlight potential costs.