Molecular sensors for metabolic programming of the sperm epigenome and offspring physiology

项目摘要/摘要 最近的研究已经证实，从父亲那里继承的表观遗传信息对 他的孩子的生理状况，这一信息取决于环境暴露和 父亲的新陈代谢状态。现在也有大量的证据表明，父系遗传 表观遗传信息可能会导致儿童肥胖和其他重大公共卫生问题， 取决于父亲的饮食。然而，机械论的见解仍然很少，而且还不清楚是哪种饮食 因子可能能够以一种影响精子新陈代谢的方式改变精子的表观遗传编程 后代。为了解决这个重要的问题，这个项目将检验这样一个中心假设，即减少父性 代谢烟酰胺腺嘌呤二核苷酸(NAD+)水平导致可遗传的精子携带的表雄化 来调节后代的新陈代谢。NAD+是参与能量代谢的中心分子，它还 作为表观遗传调节剂的底物，如sirtuins，包括组蛋白脱乙酰基酶和聚(ADP- 核糖)聚合酶参与精子的表观遗传编程和能量代谢的调节。 维生素B3(烟酸、烟酰胺)是人类NAD+合成的主要膳食前体。这个项目 建议利用获得性烟酸缺乏(Andy)的创新转基因小鼠模型，允许 首次在实验室研究低NAD+水平的影响，如在部分人群中看到的那样 动物。我们的初步数据显示，安迪雄性体内NAD+水平低于最佳水平会导致后代患有 体型较小，胰岛素敏感性改变，碳水化合物和脂肪代谢改变，这表明 微量营养素烟酸可能具有以前未被认识到的重要性 精子。拟议工作的目标是(1)描述NAD+缺乏的男性的新陈代谢 以及他们的F1后代，我们希望在那里识别依赖于 父亲的营养状况，(2)检验男性低NAD+水平会导致精子增加的假设 组蛋白乙酰化和差异精子组蛋白定位，预计将包括代谢基因 以及(3)确定基因改变的性质和程度 F_1代的基因表达谱。我们还建议确定药理作用的程度 干预措施，例如补充疗法，可以防止这种变化。 我们预计，DNA甲基化水平将在后代的基因座位上发生改变 NAD+缺乏的父本精子组蛋白乙酰化异常。总而言之，拟议的研究预计将 建立NAD+作为父亲营养和代谢状态之间的分子联系，精子染色质介导 表观遗传和后代代谢的调节，包括代谢性疾病。预期中的 研究结果应与避免和妊娠周营养的未来发展相关 针对男性的补充策略，目的是最大限度地增加孩子出生时健康的机会。

Project Summary / Abstract Recent research has established that epigenetic information inherited from the father has an impact on the physiology of his children, and that this information varies depending on environmental exposure and metabolic status of the father. There is also now a substantial body of evidence that paternally inherited epigenetic information may contribute to childhood obesity and other significant public health problems, depending on paternal diet. Mechanistic insights are still scarce, however, and it remains unclear which dietary factors may be able to modify epigenetic programming of sperm in a way that affects metabolism in the offspring. Addressing this important problem, this project will test the central hypothesis that reduced paternal metabolic nicotinamide adenine dinucleotide (NAD+) levels result in heritable sperm-borne epimodifications that modulate offspring metabolism. NAD+ is a central molecule involved in energy metabolism and it also serves as a substrate of epigenetic regulators such as sirtuins, including histone deacetylases, and poly(ADP- ribose) polymerases involved in sperm epigenetic programming and the regulation of energy metabolism. Vitamin B3 (niacin, nicotinamide) is the main dietary precursor of NAD+ synthesis in humans. This project proposes to utilize an innovative transgenic mouse model of acquired niacin deficiency (ANDY) that permits for the first time to study effects of low NAD+ levels, as seen in parts of the human population, in a laboratory animal. Our preliminary data show that suboptimal levels of NAD+ in ANDY males resulted in progeny with smaller body size, altered insulin sensitivity, and altered carbohydrate and lipid metabolism, which indicates that the micronutrient niacin may be of previously unrecognized importance for epigenetic programming of sperm. The objectives of the proposed work are (1) to characterize the metabolism of NAD+-deficient males and their F1 progeny, where we expect to identify heritable adaptations of energy metabolism that depend on paternal nutritional status, (2) to test the hypothesis that low NAD+ levels in males result in elevated sperm histone acetylation and differential sperm histone positioning, which are expected to include metabolic genes whose regulation is affected in F1 progeny, and (3) to determine the nature and extent of altered gene expression profiles in F1 progeny. We further propose to determine the extent to which pharmacological intervention, e.g. supplementation therapy, can prevent such changes. We expect that DNA methylation levels will be altered in gene loci in offspring as a consequence of abnormal sperm histone acetylation in NAD+-deficient sires. In summary, the proposed studies are expected to establish NAD+ as a molecular link between paternal nutrition and metabolic state, sperm chromatin-mediated epigenetic inheritance, and the regulation of offspring metabolism, including metabolic disease. The expected results should be relevant for the future development of avoidance and periconceptional nutritional supplementation strategies for men with the goal to maximize chances that children are born healthy.