Dietary Supplements, Imprint Gene Expression and Cancer

描述(申请人提供)：越来越多的证据表明，成人癌症的发病机制可能会受到生命早期营养的影响。一个可能的潜在机制是通过表观遗传学的早期营养效应，即不依赖于DNA序列的自我永久化的基因调控系统。一个特别相关的表观遗传机制涉及回文CpG二核苷酸的两条链上的胞嘧啶残基的甲基化。哺乳动物的一碳代谢为生物甲基化反应提供甲基，高度依赖于饮食底物和辅因子。因此，在发育早期建立和维持基因组甲基化模式的要求，可能使得在那个时期保持这些饮食衍生成分的适当水平比在以后的生活中更关键。我们已经证明，在存活的黄色刺鼠(A{vy})小鼠的早期发育过程中，在饮食中添加额外的叶酸、维生素B12、胆碱和甜菜碱，可以通过增加刺鼠基因CpG甲基化来改变毛色。拟议研究的总体假设是，母体膳食甲基供体补充可以改变早期胚胎中印记基因的DNA甲基化，并且这些诱导的表观遗传改变持续影响成人癌症的易感性。拟议研究的具体目的是：1)确定妊娠期和哺乳期膳食甲基供体补充是否改变后代对致癌杂环胺苯基咪唑[4，5-b]吡啶(PhlP)的易感性，2)确定妊娠期和哺乳期膳食甲基供体补充是否改变印记胰岛素样生长因子2(Lgf2)基因的等位基因表达和等位基因特异性甲基化，以及3)确定其他印迹基因的甲基化和等位基因表达因妊娠期和哺乳期补充膳食甲基供体而改变。由于基因组印迹的表观遗传失调与广泛的人类发育障碍和癌症有关，了解将产前营养与成人印记基因表达联系起来的特定生物机制可能最终使早期营养干预能够预防人类成年后癌症的发生。

DESCRIPTION (provided by applicant): There is accumulating evidence that the pathogenesis of adult cancer can be influenced by nutrition in early life. One probable underlying mechanism is through early nutritional effects on epigenetics, i.e. self perpetuating gene regulatory systems that are not dependent on DNA sequence. A particularly relevant epigenetic mechanism involves the methylation of cytosine residues on both strands of palindromic CpG dinucleotides. Mammalian one-carbon metabolism, which provides the methyl groups for biological methylation reactions, is highly dependent on dietary substrates and co-factors. Thus, the requirement to establish and maintain genomic methylation patterns during early development may make it more critical to maintain appropriate levels of these diet-derived components at that time than during later life. We have demonstrated that dietary methyl donor supplementation with extra folic acid, vitamin B12, choline and betaine during early development of viable yellow agouti (A {vy}) mice alters coat color by increasing CpG methylation at the agouti locus. The overall hypothesis of the proposed research is that maternal dietary methyl donor supplementation can alter DNA methylation of imprinted genes in the early embryo, and that these induced epigenetic alterations persist to influence adult cancer susceptibility. The specific aims of the proposed research are to: 1) determine if maternal dietary methyl donor supplementation during pregnancy and lactation alters breast cancer susceptibility in the offspring to the carcinogenic heterocyclic amine, phenyl-imidazol [4,5-b] pyridine (PhlP), 2) determine if maternal dietary methyl donor supplementation during pregnancy and lactation alters allelic expression and allele-specific DNA methylation of the imprinted insulin-like growth factor 2 (lgf2) gene, and 3) identify other imprinted genes whose methylation and allelic expression are altered by maternal dietary methyl donor supplementation during pregnancy and lactation. Because epigenetic dysregulation of genomic imprinting is implicated in a broad range of human developmental disorders and cancer, understanding the specific biologic mechanisms linking prenatal nutrition to adult expression of imprinted genes may ultimately enable early-life nutritional interventions to prevent adult-onset cancer in humans.