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。甲基供体的膳食摄入量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人类疾病，特别是癌症的风险是如何受到表观遗传学和饮食的影响的。我们使用了A10-vy（肥胖黄色）小鼠，这是一种表现出肥胖、肿瘤和II型糖尿病高度可变表型的模型；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是可以遗传的，这表明决定等位基因行为的表观遗传标记在种系中是保持的。在妊娠期间，母体A-vy饮食中添加甲基供体会改变后代的表型。我们假设，母体饮食中持续补充甲基供体会导致a -vy等位基因甲基化的累积增加，导致肥胖黄色表型的抑制和等位基因的密集甲基化的多代趋势。在停止补充后，这些变化可能持续存在。我们的具体目标是：1。探讨持续补充甲基供体对A-vy小鼠肥胖黄表型遗传的影响。持续给A-vy母亲喂食甲基供体可能会产生表型变化，这种变化随着代的增加而增加。2. 询问甲基供体补充的影响在停止补充后是否会持续几代。甲基供体引起的变化可能在种系中保持，导致持续一代或多代的表观遗传“记忆”。3. 研究甲基供体补充对a -vy等位基因CpG甲基化的影响我们将使用亚硫酸盐等位基因测序来获得为Aims 1和2饲养的小鼠中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 The changes may persist after supplementation is withdrawn.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 Ask if the effects of methyl donor supplementation persist for generations when supplementation is withdrawn.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.