Epigenetics of Dietary and Body Fat in Drosophila

果蝇膳食和体脂肪的表观遗传学

• 批准号: 7314106
• 负责人: Douglas M Ruden
• 金额: $ 10.24万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2008-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7314106
• 关键词: DNA methylation; Drosophilidae; RNA interference; acetylation; adipose tissue; binding sites; caloric dietary content; chromatin; chromatin immunoprecipitation; dietary lipid; dietary restriction; genetic mapping; genetic markers; genetic regulation; genetic susceptibility; histones; laboratory mouse; longevity; microarray technology; neoplasm /cancer genetics; nutrition related tag; oncogenes; polymerase chain reaction; prostate neoplasms; protein structure; telomerase

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.

描述（由申请人提供）： 热量限制会降低小鼠癌症的发病率并延迟其发病时间。热量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。这些模式生物的结果表明，各种组蛋白脱乙酰酶具有不同的靶基因组和乙酰化组蛋白的不同特异性，这些乙酰化组蛋白激活或失活这些基因上的染色质。热量限制会导致能量摄入、能量消耗和体脂减少，但最近的实验表明，胰岛素受体基因敲除小鼠的能量摄入、能量消耗增加，而且矛盾的是，寿命也增加了。这些研究表明，身体脂肪和膳食脂肪作为长寿和癌症进展的决定因素比能量摄入或消耗更有意义。基于上述观察，该提案的主要假设是，低身体脂肪和膳食脂肪会改变关键癌症基因的染色质状态，从而降低患癌症的倾向，相反，高身体脂肪和膳食脂肪会改变关键癌症基因的染色质状态，从而增加患癌症的倾向。第二个假设是，这些关键基因在小鼠和果蝇之间是保守的，并且比较这两种生物体中染色质以类似方式受到影响的基因将有助于识别人类中的前列腺癌易感基因。目标是： 1) 在一项多代研究中鉴定染色质状态改变的基因（改变的 Rpd3 或 Sir2 结合位点），其中高或低体脂同基因菌株的果蝇被喂食低脂肪（高碳水化合物）或高脂肪（美国混合脂肪，低碳水化合物）饮食； 2) 确定减少 Hsp90、Src、Rpd3、Sir2 和目标 1 中确定的一些果蝇基因的数量是否会改变饲喂低脂肪或高脂肪饮食的果蝇的寿命和染色质模式； 3) 为了表征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），以及目标 1 中确定的基因的一些同源物，在 24 摄氏度（必须消耗能量以维持体温的条件）或 35 摄氏度（ 小鼠的热中性温度）。该提案完成后，通过明智地使用比较果蝇遗传学，将鉴定出一些染色质改变的基因，这些基因会影响果蝇、小鼠和人类的癌症倾向和寿命。