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

表观遗传是亲代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，父母或祖父母暴露在饥饿、创伤、香烟烟雾或其他应激源下会改变子女对心血管疾病、肥胖症、肺部疾病或其他疾病的易感性。对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父母传给后代的潜在机制提供了工具。这种研究在很大程度上得益于最近的技术进步，包括下一代测序和微小RNA生物学等基础发现。体外受精实验表明，精子携带了足够的信息来在世代之间传播表观遗传表型，而对这些父系表观遗传模型的研究发现，精子相关小非编码RNA(SncRNA)是从父亲到后代的信息载体。我已经建立了一个表观遗传模型，在这个模型中，父亲的流感感染，随着病毒的清除和交配前的疾病恢复，导致后代因流感感染而疾病严重程度的适应性减弱(体重显著减少)，以及不适应的葡萄糖代谢变化。虽然这些表型是健壮的，但将信息传递给后代的潜在机制 仍有待确定。在解决这一机制的初步实验中，我发现流感感染会改变精子相关的SncRNA。这一建议解决了一种假设，即流感病毒诱导的精子相关SNcRNA群体的变化会改变胚胎发育，从而导致后代的代谢和免疫表型。目的1通过对精子SNcRNA和早期胚胎发育的动力学分析，阐明其潜在的表观遗传机制。目的2通过直接挑战无交叉反应的流感病毒株，间接通过进一步的代谢表型分型来确定子代表观遗传表型对父亲应激源的特异性，以确定父源流感感染是否以类似于其他父源应激源的方式改变子代的葡萄糖稳态和肝脏基因表达。这项研究将为表观遗传的潜在机制提供有价值的见解，并在一种与人类健康直接相关的新表观遗传模型的背景下做到这一点。

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.