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

项目概要/摘要 最近的研究表明，从父亲那里继承的表观遗传信息会对孩子产生影响。 他的孩子的生理机能，并且这些信息根据环境暴露和变化而变化 父亲的代谢状况。现在还有大量证据表明父系遗传 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， 取决于爸爸的饮食。然而，机制见解仍然很少，目前还不清楚哪种饮食 因素可能能够以影响精子代谢的方式改变精子的表观遗传编程。 后代。为了解决这个重要问题，该项目将检验减少父系遗传的中心假设。 代谢烟酰胺腺嘌呤二核苷酸 (NAD) 水平导致可遗传的精子传播表观修饰 调节后代新陈代谢。 NAD是参与能量代谢的中心分子， 作为表观遗传调节因子的底物，例如去乙酰化酶，包括组蛋白脱乙酰酶和聚（ADP- 核糖）聚合酶参与精子表观遗传编程和能量代谢的调节。 维生素 B3（烟酸、烟酰胺）是人体 NAD 合成的主要膳食前体。这个项目 提议利用获得性烟酸缺乏症（ANDY）的创新转基因小鼠模型，该模型允许 首次在实验室中研究低 NAD 水平的影响（如在部分人群中所见） 动物。我们的初步数据表明，ANDY 雄性中 NAD 水平欠佳导致后代患有 身体尺寸变小，胰岛素敏感性改变，碳水化合物和脂质代谢改变，这表明 微量营养素烟酸对于表观遗传编程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) 表征 NAD 缺乏的男性的新陈代谢 及其 F1 后代，我们期望在其中识别依赖于能量代谢的可遗传适应 父亲的营养状况，(2) 检验男性 NAD 水平低导致精子增多的假设 组蛋白乙酰化和差异精子组蛋白定位，预计包括代谢基因 其调节在 F1 后代中受到影响，以及 (3) 确定改变基因的性质和程度 F1 后代中的表达谱。我们进一步建议确定药理学的程度 干预，例如补充疗法，可以预防这种变化。 我们预计，由于以下原因，后代基因座中的 DNA 甲基化水平将发生改变： NAD 缺陷公牛的精子组蛋白乙酰化异常。总之，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，以及后代代谢的调节，包括代谢疾病。预期的 结果应与回避和围孕期营养的未来发展相关 男性补充策略，旨在最大限度地提高孩子健康出生的机会。

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.