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

急性父亲应激小鼠模型的表观遗传机制

• 批准号: 10023932
• 负责人: Noah Jacob Silverstein
• 金额: $ 3.03万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10023932
• 关键词: Acute; Address; Affect; Animal Model; Animals; Attenuated; Biology; Body Weight decreased; Cardiovascular Diseases; Chronic; Chronic stress; Conceptions; Development; Disease; Disease Resistance; Embryo; Embryonic Development; Environmental Risk Factor; Epigenetic Process; Exposure to; Fathers; Female; Fertilization in Vitro; Foundations; Future Generations; Gene Expression; Generations; Health; Human; Immune; Implant; Infection; Influenza; Intervention; Investigation; Kinetics; Liver; Lung diseases; Mentors; Metabolic; Metabolism; MicroRNAs; Modeling; Nature; Nicotine; Obesity; Parents; Partner in relationship; Pathologic; Phenotype; Physiological; Poison; Population; Predisposition; Preimplantation Diagnosis; Process; Publishing; Recovery; Reporting; Research; Resistance; Role; Route; Severity of illness; Specificity; Starvation; Stress; Time; Tissues; Trauma; Untranslated RNA; Virus; Virus Diseases; Weight; attenuation; blastocyst; blood glucose regulation; cigarette smoke; disorder risk; environmental stressor; epidemiology study; experimental study; fasting glucose; flu; glucose metabolism; grandparent; influenza virus strain; influenzavirus; insight; male; metabolic phenotype; mouse model; next generation sequencing; nicotine exposure; novel; offspring; pathogen; physiologic stressor; response; sperm analysis; sperm cell; stressor; tool; transcriptome

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.

表观遗传是指亲本暴露于环境因素影响后代表型的过程。这一研究领域对人类健康有着广泛的影响。流行病学研究表明，父母或祖父母暴露于饥饿、创伤、吸烟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父母传递到后代的潜在机制提供了工具。最近的技术进步，包括下一代测序和microRNA生物学等基础发现，极大地促进了此类研究。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，并且对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）作为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，在该模型中，父亲流感感染，在交配前病毒消除和疾病恢复，导致后代对流感感染的适应性疾病严重程度减轻（体重减轻显著减少），以及适应不良的葡萄糖代谢改变。虽然这些表型是强大的，但信息传递给后代的潜在机制 还有待确定。在解决该机制的初步实验中，我发现流感感染会改变精子相关sncRNA。这一提议提出了这样一个假设，即流感病毒诱导的精子相关sncRNA群体的变化改变了胚胎发育，导致后代代谢和免疫表型。目的1通过对精子sncRNA和早期胚胎发育的动力学分析，阐明表观遗传学机制。目的2确定后代表观遗传表型对父亲压力源的特异性，直接通过用流感病毒的非交叉反应株进行攻击，间接通过进一步代谢表型分析以确定父亲流感感染是否以类似于其他父亲压力源的方式改变后代中的葡萄糖稳态和肝脏基因表达。这项研究将为表观遗传的机制提供有价值的见解，并在与人类健康直接相关的新型表观遗传模型的背景下这样做。