Diet, Epigenetic Events, And Cancer Prevention

描述(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。甲基供体的饮食摄入可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表观遗传学和饮食如何影响人类疾病，特别是癌症的风险。我们使用了一只10-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是可以遗传的，表明决定等位基因行为的表观遗传标记在种系中保持不变。在怀孕期间补充母体A-VY饮食中的甲基供体会改变后代的表型。我们假设，持续补充含有甲基供体的母体饮食将产生A-vy等位基因甲基化的累积增加，导致多代人的趋势是抑制肥胖的黄色表型，并使该等位基因的甲基化更加密集。在撤回补充后，这些变化可能会持续下去。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。将甲基供体持续喂养给A-VY母亲可能会产生表型变化，这种变化会随着世代的增加而增加。2.询问当停止补充甲基供体时，甲基供体补充的影响是否会持续几代人。由甲基供体引起的变化可能会在生殖系中保持，导致表观遗传的“记忆”持续一代或更多代。3.研究补充甲基供体对A-vy等位基因CpG甲基化的影响我们将使用亚硫酸氢盐等位基因测序，以获得AIMS 1和2所育小鼠该等位基因甲基化状态的详细图像。

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 The changes may persist after supplementation is withdrawn.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 Ask if the effects of methyl donor supplementation persist for generations when supplementation is withdrawn.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.