Dietary Supplements, Imprint Gene Expression and Cancer

描述（由申请人提供）：越来越多的证据表明，成人癌症的发病机制可能受到早期营养的影响。一个可能的潜在机制是通过早期营养对表观遗传学的影响，即不依赖于DNA序列的自我延续基因调控系统。一个特别相关的表观遗传机制涉及回文CpG二核苷酸两条链上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，高度依赖于膳食底物和辅助因子。因此，在早期发育过程中建立和维持基因组甲基化模式的要求可能使得在那时保持这些饮食来源的组分的适当水平比在以后的生活中更重要。我们已经证明，膳食甲基供体补充额外的叶酸，维生素B12，胆碱和甜菜碱在早期发展的可行的黄色琼脂糖（A {vy}）小鼠改变毛色增加CpG甲基化在琼脂糖位点。这项研究的总体假设是，母体膳食甲基供体补充剂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学改变持续影响成人癌症易感性。拟议研究的具体目标是：1）确定在妊娠和哺乳期间母体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（PhIP）的乳腺癌易感性，2）确定在怀孕和哺乳期间母体膳食甲基供体补充是否改变等位基因表达和等位基因-印迹胰岛素样生长因子2（lgf 2）基因的特异性DNA甲基化，和3）鉴定其甲基化和等位基因表达在妊娠和哺乳期间通过母体膳食甲基供体补充而改变的其它印迹基因。由于基因组印记的表观遗传失调与广泛的人类发育障碍和癌症有关，因此了解将产前营养与印记基因的成人表达联系起来的特定生物学机制可能最终使早期生活营养干预能够预防人类成人发病的癌症。

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.