Epigenetic Suppression of the Obese Yellow Phenotype

肥胖黄色表型的表观遗传抑制

• 批准号: 7102832
• 负责人: David Ian Kingston Martin
• 金额: $ 30.88万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102832
• 关键词: CpG islands; alleles; cancer prevention; cancer risk; cytosine; dietary supplements; gene induction /repression; laboratory mouse; methylation; nucleic acid sequence; nutrition aspect of cancer; nutrition related tag; obesity; phenotype

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 The changes may persist after supplementation is withdrawn.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 Ask if the effects of methyl donor supplementation persist for generations when supplementation is withdrawn.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

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 A10-vy（肥胖黄）小鼠，该模型表现出高度可变的肥胖、肿瘤和 II 型糖尿病表型；该综合征的表达受到表观遗传的控制。 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保留。在妊娠期间向母体 A-vy 饮食中补充甲基供体会改变后代的表型。我们假设，在母体饮食中持续补充甲基供体将导致 A-vy 等位基因的甲基化累积增加，从而导致抑制肥胖黄色表型和等位基因更密集甲基化的多代趋势。撤回补充后，这些变化可能会持续存在。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 A-vy 母亲的甲基供体可能会产生表型变化，这种变化随着世代的增加而增加。 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能会保留在种系中，从而导致表观遗传“记忆”持续一代或多代。 3. 研究甲基供体补充对 A-vy 等位基因 CpG 甲基化的影响 我们将使用亚硫酸氢盐等位基因测序来获得针对目标 1 和 2 培育的小鼠中等位基因甲基化状态的详细图片。