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: 10614492
• 负责人: Mirella L Meyer-Ficca
• 金额: $ 30.85万
• 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/10614492
• 关键词: Acceleration; Acetyl Coenzyme A; Acetylation; Address; Adipose tissue; Affect; Aging; Antibodies; Birth; Body Size; Carbohydrates; Cells; Child; Chromatin; Conceptions; 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; 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; 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; pharmacologic; 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.

项目总结/摘要 最近的研究已经确定，从父亲那里继承的表观遗传信息对孩子的发育有影响。 他的孩子的生理学，这一信息取决于环境暴露， 父亲的代谢状态现在也有大量的证据表明父亲遗传了 表观遗传信息可能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，机制的见解仍然很少，并且仍然不清楚哪些饮食 这些因素可能能够改变精子的表观遗传编程，从而影响精子中的代谢。 后代为了解决这一重要问题，该项目将测试中心假设，减少父亲的 代谢的烟酰胺腺嘌呤二核苷酸（NAD+）水平导致可遗传的精子传播的表观修饰 来调节后代的新陈代谢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，如沉默调节蛋白，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）是人体合成NAD+的主要饮食前体。这个项目 提出利用一种创新的获得性烟酸缺乏症（ANDY）转基因小鼠模型， 第一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+的次优水平导致后代具有以下特征： 更小的体型，改变胰岛素敏感性，改变碳水化合物和脂质代谢，这表明 微量营养素烟酸可能是以前未认识到的重要性表观遗传编程 精子本研究的主要目的是：（1）研究NAD+缺乏男性的代谢特征 和他们的F1后代，我们希望在那里确定能量代谢的遗传适应， 父亲的营养状况，（2）检验男性低NAD+水平导致精子升高的假设 组蛋白乙酰化和差异精子组蛋白定位，预计包括代谢基因 其调控在F1后代中受到影响，以及（3）确定改变的基因的性质和程度 F1代的表达谱。我们进一步建议确定药物在多大程度上 干预，例如补充疗法，可以防止这种变化。 我们预计，DNA甲基化水平将改变基因位点的后代作为一个后果， NAD+缺乏公牛精子组蛋白乙酰化异常。总之，拟议的研究预计将 建立NAD+作为父系营养和代谢状态之间分子联系，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 结果应该是相关的未来发展的回避和围概念营养 针对男性的补充战略，目的是最大限度地增加儿童健康出生的机会。