Diet, Epigenetic Events, And Cancer Prevention

描述（由申请人提供）：在癌症中，正常的表观遗传沉默和胞嘧啶甲基化被破坏。膳食摄入甲基供体可以通过胞嘧啶甲基化直接影响表观遗传机制。我们的长期目标是了解人类疾病，特别是癌症的风险如何受到表观遗传学和饮食的影响。我们使用A10-vy（肥胖黄色）小鼠，这是一种表现出高度可变的肥胖、肿瘤和II型糖尿病表型的模型;该综合征的表达受表观遗传控制。A-vy等位基因的表观遗传状态可以遗传，表明决定等位基因行为的表观遗传标记在种系中得以维持。在妊娠期间补充母亲的A-vy饮食与甲基供体改变后代的表型。我们假设，母亲饮食中持续补充甲基供体将产生A-vy等位基因甲基化的累积增加，导致肥胖黄色表型抑制的多代趋势，以及等位基因的密集甲基化。这些变化可能在补充剂停止后持续存在。我们的具体目标是：1.研究持续补充甲基供体对A-vy小鼠肥胖黄色表型遗传的影响。连续喂养甲基供体的A-vy母亲可能会产生表型的变化，增加更多的代。2.询问当停止补充时，甲基供体补充的影响是否会持续几代人。甲基供体诱导的变化可以保持在生殖系中，导致表观遗传“记忆”持续一个或多个世代。3.研究甲基供体补充对A-vy等位基因的CpG甲基化的影响我们将使用亚硫酸氢盐等位基因测序来获得针对目的1和2饲养的小鼠中等位基因的甲基化状态的详细图片。

DESCRIPTION (provided by applicant): In cancer, normal epigenetic silencing and cytosine methylation are disrupted. Dietary intake of methyl donors can directly affect epigenetic mechanisms through cytosine methylation. Our longterm goal is to understand how the risk of human disease, cancer in particular, is affected by epigenetics and diet. We use A10-vy (obese yellow) mice, a model that exhibits a highly variable phenotype of obesity, tumors, and type II diabetes; the expression of the syndrome is under epigenetic control. The epigenetic state of the A-vy allele can be inherited, indicating that the epigenetic marks determining the behavior of the allele are maintained in the germline. Supplementation of the maternal A-vy diet with methyl donors during gestation alters phenotypes in offspring. We hypothesize that continuous supplementation of the maternal diet with methyl donors will produce a cumulative increase in methylation of the A-vy allele, resulting in a multigenerational trend toward suppression of the obese yellow phenotype, and denser methylation of the allele. The changes may persist after supplementation is withdrawn. Our specific aims are: 1. Investigate the effects of continuous methyl donor supplementation on inheritance of the obese yellow phenotype in A-vy mice. Continuous feeding of methyl donors to A-vy mothers may produce changes in phenotype that increase with more generations. 2. Ask if the effects of methyl donor supplementation persist for generations when supplementation is withdrawn. Changes induced by methyl donors may be maintained in the germline, resulting in epigenetic "memory" that persists for one or more generations. 3. Investigate effects of methyl donor supplementation on CpG methylation of the A-vy allele We will use bisulphite allelic sequencing to obtain a detailed picture of the methylation status of the allele in mice bred for Aims 1 and 2.