Epigenetic regulation of metabolism in Drosophila

果蝇代谢的表观遗传调控

• 批准号: 8723817
• 负责人: CARL S. THUMMEL
• 金额: $ 28.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-20 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723817
• 关键词: Adult; Adult Children; Animals; Area; Biological Assay; Biological Models; Biomedical Research; Cardiovascular Diseases; Chromatin; Complex; Correlative Study; Defect; Diabetes Mellitus; Diet; Disease; Drosophila genus; Employee Strikes; Epidemic; Epidemiologic Studies; Epigenetic Process; Evolution; Fatty acid glycerol esters; Female; Frequencies; Functional disorder; Generations; Genes; Genetic; Genetic screening method; Goals; Health; Homeostasis; Human; Hunger; Inherited; Lead; Link; Literature; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Modeling; Molecular; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Nutritional; Obesity; Organism; Parents; Pathway interactions; Pattern; Phenotype; Physiological; Play; Population; Public Policy; Rattus; Regulation; Reporting; Research; Risk; Rodent; Series; Surveys; Testing; Time; Tissues; Work; base; chromatin modification; combat; feeding; fly; genome-wide; histone modification; human disease; improved; male; metabolic abnormality assessment; metabolomics; mutant; offspring; public health relevance; research study; response; sex; stem; transcriptome sequencing; transmission process

DESCRIPTION (provided by applicant): The alarming rise in the frequency of diabetes and obesity in worldwide populations has prompted major changes in public policy as well as a shift in biomedical research toward improving our understanding of how misregulation of metabolism can lead to disease. Central to this epidemic of metabolic disorders is the striking correlation between the metabolic health of the parents and that of their offspring. There is a vast literature describing this phenomenon in rats and mice, demonstrating that temporary nutritional changes in the parental generation can have major effects on the metabolic status of their adult offspring maintained on a normal diet. This includes an increased risk for developing type 2 diabetes and obesity. Epidemiological studies of adults born during the Dutch Hunger Winter of 1944, along with other more correlative studies, have demonstrated that similar inherited effects on metabolism can be seen in humans. Molecular studies have shown that changes in epigenetic chromatin marks in offspring are associated with changes in parental diet, providing a potential molecular mechanism to explain the inherited effects on metabolism. In spite of these extensive studies, however, the research in this area remains correlative. Only a few genetic approaches have been used to characterize the inheritance of metabolic state, and there is no defined molecular mechanism to explain this association. We have discovered that the fruit fly Drosophila shares the ability to link the metabolic status of parents with that of their offspring, that transmission can be seen through both the male and female germline, that metabolic dysfunction carries through to the F2 and F3 generations, and that the phenotypes are similar to those reported in rodent and human studies. We have identified a nuclear receptor that contributes to this response, DHR96, and have shown that genetic changes in epigenetic state can lead to metabolic dysfunction in the offspring. We propose here two specific aims to extend these initial observations. First, we will define the physiological and metabolic defects seen in the adult offspring of parents subjected to different transient dietary treatments. These experiments will include metabolomic profiling, transcriptional profiling by RNA-seq, tissue-specific and sex-specific genetic studies, and testing different dietary treatments. Second, we will characterize the epigenetic regulation of transgenerational metabolic control by determining the genome- wide changes in key histone modifications in the parental germline and mature adult offspring of wild-type parents subjected to different diets. We will also perform focused genetic studies to test specific models for metabolic dysfunction that arise from this work. Our goal in this research is to exploit the genetic strengths of Drosophila for studies of metabolic regulation and epigenetic control, providing, for the first time, a simple model system to define the molecular mechanisms that control transgenerational metabolic inheritance.

描述（由申请人提供）：全球人口中糖尿病和肥胖症的频率令人震惊，这引发了公共政策的重大变化，以及生物医学研究的转变，以提高我们对新陈代谢不正常的理解可能导致疾病的理解。这种代谢性疾病流行的核心是父母的代谢健康与后代的新陈代谢健康之间的显着相关性。有大量文学 描述大鼠和小鼠中的这种现象，表明父母产生的暂时营养变化会对其成年后代的代谢状况产生重大影响。这包括增加2型糖尿病和肥胖症的风险。 1944年荷兰饥饿冬季出生的成年人的流行病学研究以及其他更相关的研究表明，在人类中可以看到对代谢的类似遗传作用。分子研究表明，后代表观遗传染色质标记的变化与父母饮食的变化有关，从而提供了一种潜在的分子机制来解释遗传对代谢的遗传作用。但是，尽管进行了这些广泛的研究，但该领域的研究仍然相关。仅使用了几种遗传方法来表征代谢状态的遗传，并且没有确定的分子机制来解释这种关联。我们已经发现，果蝇果蝇具有将父母代谢地位与他们的后代的代谢状况联系起来的能力， 可以通过男性和女性种系观察到这种传播，代谢功能障碍将传播到F2和F3世代，并且表型与啮齿动物和人类研究中报道的表型相似。我们已经确定了有助于这种反应的核受体DHR96，并表明表观遗传状态的遗传变化会导致后代的代谢功能障碍。我们在这里提出了两个特定目的，以扩展这些初始观察。首先，我们将定义在经受不同瞬时饮食治疗的父母后代中看到的生理和代谢缺陷。这些实验将包括代谢组分析，通过RNA-Seq进行转录分析，组织特异性和性别特异性遗传研究以及测试不同的饮食治疗。其次，我们将通过确定父母种系中关键组蛋白修饰的基因组的广泛变化和野生型父母的成熟成人后代的基因组发生变化，来表征转世代谢控制的表观遗传调节。我们还将进行重点的遗传研究，以测试由这项工作引起的代谢功能障碍的特定模型。这项研究的目标是利用果蝇的遗传强度来研究代谢调节和表观遗传控制，这是第一次提供一个简单的模型系统来定义控制转世代谢遗传的分子机制。