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

用于精子表观基因组和后代生理学代谢编程的分子传感器

• 批准号: 10383731
• 负责人: Mirella L Meyer-Ficca
• 金额: $ 30.87万
• 依托单位: UTAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383731
• 关键词: Acetyl Coenzyme A; Address; Adipose tissue; Affect; Aging; Antibodies; Birth; Body Size; Carbohydrates; Cells; ChIP-seq; Child; Chromatin; DNA Methylation; Data; Development; Diet; Dietary Factors; Energy Metabolism; Environmental Exposure; Enzymes; Epigenetic Process; Exhibits; Fathers; Fatty acid glycerol esters; Fertility; Future; Gene Expression; Genes; Glucose; Goals; Growth; Health; Heritability; High-Throughput DNA Sequencing; Histone Acetylation; Histone Deacetylase; Histone H4; Histones; Human; Infertility; Inherited; Intake; Intervention; Laboratory Animals; Link; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Micronutrients; Modeling; Modification; Molecular; Mus; NADP; National Institute of Child Health and Human Development; Nature; Niacinamide; Nicotinamide adenine dinucleotide; Nicotinic Acids; Nutritional status; Oxygen Consumption; Pharmacology; Phenotype; Physical activity; Physiology; Poly(ADP-ribose) Polymerases; Population; Positioning Attribute; Public Health; Pyruvate; Regulation; Reporting; Research; Respiration; Role; Sirtuins; Spermatogenesis; Strategic Planning; Supplementation; Testing; Time; Transgenic Mice; Work; base; carbohydrate metabolism; chromatin immunoprecipitation; chromatin modification; chromatin remodeling; dietary; differential expression; epigenome; genetic risk factor; genomic locus; histone acetyltransferase; histone modification; innovation; insight; insulin sensitivity; interest; lean body mass; lipid metabolism; male; men; mouse model; nutrition; nutritional supplementation; obesity in children; offspring; prevent; programs; respiratory; sensor; sperm cell

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.

项目摘要 /摘要 最近的研究表明，父亲继承的表观遗传信息对 他的孩子的生理学，此信息因环境暴露和 父亲的代谢地位。现在也有大量证据表明父亲是继承的 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， 取决于父亲饮食。然而，机械洞察力仍然很少，尚不清楚哪种饮食 因素可能能够以影响新陈代谢的方式修改精子的表观遗传编程 后代。解决这个重要问题，该项目将测试中心假设，即减少父亲 代谢烟酰胺腺嘌呤二核苷酸（NAD+）水平导致可遗传的精子培养 这种调节后代代谢。 NAD+是参与能量代谢的中央分子，也是如此 用作表观遗传调节剂（例如sirtuins）的底物，包括组蛋白脱乙酰基酶和poly（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）是人类NAD+合成的主要饮食前体。这个项目 建议利用获得的烟酸缺乏症（Andy）的创新转基因小鼠模型，该模型允许 如在人口的部分地区所见，在实验室中，第一次研究低NAD+水平的影响 动物。我们的初步数据表明，安迪男性的NAD+次优水平导致后代 体型较小，胰岛素敏感性改变，碳水化合物和脂质代谢改变，这表明 微量营养素的烟酸可能对表观遗传编程的重要性可能是 精子。提议的工作的目标是（1）表征NAD+缺陷男性的代谢 以及他们的F1后代，我们期望确定能量代谢的可遗传适应 父亲营养状况，（2）测试了男性低NAD+水平的假设导致精子升高 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 其调节在F1后代受到影响，以及（3）确定基因改变的性质和程度 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，例如补充疗法可以防止这种变化。 我们预计，由于 NAD+缺陷式sires中异常的精子组蛋白乙酰化。总而言之，拟议的研究有望 将NAD+建立为父亲营养和代谢状态之间的分子联系，精子介导 表观遗传遗传和后代代谢的调节，包括代谢疾病。预期 结果应与未来的回避和周围营养的发展有关 为男性提供的补充策略，目的是最大程度地提高儿童天生健康的机会。