Epigenetic regulation of metabolism in Drosophila

描述(申请人提供)：全球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，生物医学研究转向提高我们对代谢调节不当如何导致疾病的理解。这种代谢性疾病流行的核心是父母的新陈代谢健康与其子女的新陈代谢健康之间存在着显著的相关性。有一部浩瀚的文献 在大鼠和小鼠身上描述了这一现象，证明父母一代的临时营养变化可以对维持正常饮食的成年后代的代谢状态产生重大影响。这包括患2型糖尿病和肥胖症的风险增加。对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，人类也可以看到类似的遗传对新陈代谢的影响。分子研究表明，后代的表观遗传染色质标记的变化与亲代饮食的变化有关，这为解释遗传对新陈代谢的影响提供了潜在的分子机制。然而，尽管有这些广泛的研究，这一领域的研究仍然是相关的。只有少数几种遗传方法被用来描述代谢状态的遗传，并且没有明确的分子机制来解释这种联系。我们发现果蝇具有将父母的代谢状态与后代的代谢状态联系起来的能力， 这种传播可以通过雄性和雌性生殖系看到，代谢障碍会传递到F2和F3代，而且表型与啮齿动物和人类研究中报告的类似。我们已经确定了一种有助于这种反应的核受体DHR96，并表明表观遗传状态的基因变化可以导致后代的代谢功能障碍。我们在这里提出了两个具体目标，以扩大这些初步观察。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出现的生理和代谢缺陷。这些实验将包括新陈代谢图谱、RNA-seq转录图谱、组织特异性和性别特异性基因研究，以及测试不同的饮食治疗。其次，我们将通过确定在不同饮食下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学调控。我们还将进行有重点的遗传学研究，以测试这项工作产生的代谢功能障碍的特定模型。我们在这项研究中的目标是利用果蝇的遗传优势来研究代谢调节和表观遗传控制，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。

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.