Epigenetic regulation of metabolism in Drosophila

果蝇代谢的表观遗传调控

基本信息

批准号：
8849437
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-20 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8849437
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 Genetic study 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 epigenetic regulation feeding fly genetic approach genome-wide histone modification human disease improved male metabolic abnormality assessment metabolomics mutant offspring research study response sex stem transcriptome sequencing transgenerational epigenetic inheritance transmission process

项目摘要

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）：全世界人口中糖尿病和肥胖症发病率的惊人上升促使公共政策发生重大变化，也促使生物医学研究转向提高我们对新陈代谢失调如何导致疾病的理解。这种代谢紊乱流行的核心是父母的代谢健康与其后代的代谢健康之间的惊人相关性。有大量的文献在大鼠和小鼠中描述了这种现象，证明父母代的暂时营养变化可能会对维持正常饮食的成年后代的代谢状态产生重大影响。这包括增加患 2 型糖尿病和肥胖的风险。对 1944 年荷兰饥饿冬季期间出生的成年人进行的流行病学研究以及其他更具相关性的研究表明，在人类中也可以看到类似的遗传对新陈代谢的影响。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，这为解释遗传对代谢的影响提供了潜在的分子机制。然而，尽管进行了这些广泛的研究，该领域的研究仍然具有相关性。只有少数遗传方法被用来表征代谢状态的遗传，并且没有明确的分子机制来解释这种关联。我们发现果蝇具有将父母的代谢状态与其后代的代谢状态联系起来的能力，可以通过雄性和雌性种系看到传播，代谢功能障碍会遗传到 F2 和 F3 代，并且表型与啮齿动物和人类研究中报道的相似。我们已经鉴定出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可能导致后代代谢功能障碍。我们在这里提出两个具体目标来扩展这些初步观察。首先，我们将定义在接受不同短暂饮食治疗的父母的成年后代中观察到的生理和代谢缺陷。这些实验将包括代谢组学分析、RNA-seq 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，我们将通过确定经历不同饮食的野生型亲本的亲本种系和成熟成年后代中关键组蛋白修饰的全基因组变化来表征跨代代谢控制的表观遗传调控。我们还将进行集中的遗传学研究，以测试这项工作中产生的代谢功能障碍的特定模型。我们这项研究的目标是利用果蝇的遗传优势来研究代谢调控和表观遗传控制，首次提供一个简单的模型系统来定义控制跨代代谢遗传的分子机制。