Mechanism of epigenetic inheritance in a mouse model of acute paternal stress

表观遗传是父母暴露于环境因素影响后代表型的过程。这一调查领域对人类健康具有广泛的影响。流行病学研究表明，父母或祖父母暴露于饥饿、创伤、香烟烟雾或其他压力因素会改变后代对心血管疾病、肥胖、肺病或其他疾病的易感性。动物模型的研究反映了这些发现，并为解开表观遗传信息从亲代传递给后代的潜在机制提供了工具。最近的技术进步极大地推动了这类研究，包括下一代测序和像microRNA生物学这样的基础发现。体外受精实验表明，精子携带足够的信息来跨代传播表观遗传表型，并且通过这些父系表观遗传模型的研究已经确定精子相关的小非编码rna （sncRNA）是父亲向后代传递信息的载体。我已经建立了一个表观遗传模型，其中父亲的流感感染，在交配前病毒消除和疾病恢复，导致后代对流感感染的疾病严重程度的适应性衰减（显著减轻体重），以及不适应的葡萄糖代谢改变。虽然这些表型是稳健的，但信息传递给后代的潜在机制

Epigenetic inheritance is a process by which parental exposure to environmental factors influences offspring phenotype. This field of investigation has wide-ranging implications for human health. Epidemiologic studies have shown that exposure of parents or grandparents to starvation, trauma, cigarette smoke, or other stressors alters offspring susceptibility to cardiovascular disease, obesity, lung disease, or other conditions. Research with animal models has mirrored these findings and offers tools for disentangling the underlying mechanisms of epigenetic information transfer from parent to offspring. Such research has been greatly enabled by recent technological advances, including next generation sequencing and fundamental discoveries like microRNA biology. In vitro fertilization experiments demonstrate that sperm carry sufficient information to propagate epigenetic phenotypes across generations, and research with these paternal epigenetic inheritance models has identified sperm-associated small non-coding RNAs (sncRNA) as carriers of information from father to offspring. I have established an epigenetic inheritance model in which paternal influenza infection, with virus elimination and disease recovery prior to mating, results in an adaptive attenuation of disease severity (significantly decreased weight loss) in response to influenza infection in offspring, as well as a maladaptive altered glucose metabolism. While these phenotypes are robust, the underlying mechanism of information transfer to offspring remains to be determined. In preliminary experiments to address the mechanism I have found that influenza infection alters sperm-associated sncRNA. This proposal addresses the hypothesis that influenza virus-induced changes in sperm-associated sncRNA populations alter embryo development resulting in offspring metabolic and immune phenotypes. Aim 1 elucidates the underlying epigenetic inheritance mechanism through kinetic analysis of sperm sncRNA and early embryo development. Aim 2 determines the specificity of the offspring epigenetic inheritance phenotype to the paternal stressor both directly by challenging with a non-cross reactive strain of influenza virus, and indirectly by further metabolic phenotyping to determine if paternal influenza infection alters glucose homeostasis and liver gene expression in the offspring in ways similar to other paternal stressors. This research will provide valuable insight into the mechanism underlying epigenetic inheritance, and do so within the context of a novel epigenetic inheritance model with direct relevance to human health.