Epigenetics of Dietary and Body Fat in Drosophila

描述(由申请人提供)： 限制卡路里摄入可降低小鼠患癌症的几率，并推迟其发病时间。卡路里限制也被证明可以延长灵长类动物、小鼠、线虫、果蝇和酵母的寿命。在这些模式生物中的结果表明，不同的组蛋白脱乙酰酶具有不同的靶基因和乙酰化组蛋白的不同特异性，这些组蛋白激活或灭活这些基因上的染色质。卡路里限制会导致能量摄入、能量消耗和身体脂肪的减少，但最近的实验表明，胰岛素受体基因敲除小鼠的能量摄入、能量消耗以及自相矛盾的是，寿命都有所增加。这些研究表明，作为长寿和癌症进展的决定因素，身体脂肪和饮食脂肪比能量摄入或消耗更有意义。基于上述观察，这项建议的主要假设是，低体脂和饮食脂肪改变了关键癌症基因的染色质状态，从而降低了癌症的倾向，反过来，高的身体和饮食脂肪改变了关键癌症基因的染色质状态，从而增加了癌症的倾向。第二种假设是，这些关键基因在老鼠和果蝇之间是保守的，比较染色质在这两种生物中以相似的方式受到影响的基因将有助于识别人类的前列腺癌易感基因。其目的是：1)在一项多代研究中识别染色质状态改变的基因(改变的Rpd3或Sir2结合位点)，在多代研究中，高或低体脂等基因系的果蝇被喂以低脂肪(高碳水化合物)或高脂肪(美国混合脂肪，低碳水化合物)；2)确定减少Hsp90，Src，Rpd3，Sir2和目标1中发现的一些果蝇基因是否改变了低脂或高脂饮食果蝇的寿命和染色质模式；3)研究端粒酶基因的染色质模式(DNA甲基化、组蛋白乙酰化和甲基化)以及在目标1中确定的一些基因的同源物，在前列腺癌小鼠模型中，无论是在24摄氏度(必须消耗能量才能维持体温)还是35摄氏度(小鼠的中温)下，喂食等卡路里的低脂肪(高碳水化合物)或高脂肪饮食(必须消耗能量以维持体温)。在这项提议完成后，通过明智地使用比较果蝇遗传学，一些染色质改变的基因将被识别出来，这些基因会影响果蝇、老鼠和人类患癌症的倾向和寿命。

DESCRIPTION (provided by applicant): Caloric restriction causes a reduction in the incidence, and a delay in the onset time of cancer in mice. Caloric restriction has also been shown to increase longevity in primates, mice, C. elegans, Drosophila, and yeast. Results in these model organisms suggest that various histone deacetylases have different sets of target genes and different specificities for acetylated histones that either activate or inactivate the chromatin on these genes. Caloric restriction causes decreases in energy intake, energy expenditure, and body fat, but recent experiments show that Insulin-Receptor knockout mice have increases in energy intake, energy expenditure, and, paradoxically, longevity. These studies suggest that body fat and dietary fat are more meaningful than energy intake or expenditure as determinants of longevity and cancer progression. The main hypothesis of this proposal, based on the above observations, is that low body fat and dietary fat alters the chromatin state of key cancer genes such that the propensity for cancer decreases, and conversely, high body and dietary fat alters the chromatin state of key cancer genes such that the propensity for cancer increases. A secondary hypothesis is that these key genes are conserved between mice and Drosophila, and that a comparison of the genes whose chromatin is affected in a similar manner in these two organisms will help to identify the prostate-cancer susceptibility genes in humans. The Aims are: 1) To identify genes with altered chromatin states (altered Rpd3 or Sir2 binding sites) in a multi-generational study in which high or low body fat isogenic strains of Drosophila are fed a low fat (high carbohydrate) or a high fat (American Blend Fat, low carbohydrate) diet; 2) To determine whether reducing the amount of Hsp90, Src, Rpd3, Sir2 and some of the Drosophila genes identified in Aim 1 alter the lifespan and the chromatin pattern of flies fed a low fat or high fat diet; and 3) To characterize the chromatin pattern (DNA methyiation, histone acetylation and methylation) of the telomerase gene, and of some of the homologs of the genes identified in Aim 1, in a mouse model of prostate cancer fed either an isocaloric low fat (high carbohydrate) or high fat diet at either 24 degrees C (a condition in which energy must be expended to maintain body temperature) or 35 degrees C (a thermoneutral temperature for mice). Upon completion of this proposal, with the judicious use of comparative Drosophila genetics, some of the genes with chromatin alterations that affect the propensity for cancer and lifespan in Drosophila, mice, and humans will be identified.