Epigenome Interactions in Complex Neurogenetic Disorders

描述(申请人提供)：DNA和染色质的修饰影响遗传密码对细胞生物机制的可及性。将表观基因组变化与神经发育障碍联系起来一直是具有挑战性的。一个障碍是需要在疾病过程的适当阶段研究相关组织，另一个障碍是难以理解核苷酸和染色质修饰与复杂的遗传疾病的关系，在复杂的遗传疾病中，多个基因位点的相互作用是疾病表达的基础。我们建议利用一种名为神经管缺陷(NTDS)的疾病，在这种疾病中，现有的小鼠模型与人类疾病密切相关，其中有几条证据表明，调节疾病表达的表观遗传修饰对小鼠和人类都有很大影响。我们将结合对小鼠的原理研究和对人类NTD队列的研究，来检查DNA/染色质甲基化与NTDS在遗传易感个体中的表达之间的关系。与其他人类疾病的表观遗传学研究相比，表观遗传学事件与其他人类疾病的研究相比具有许多明显的优势，因为人类或动物研究涉及200多个基因与NTDS有关。这些为正常神经形成的重要分子途径提供了关键线索。支持现有的临床数据，我们发现了几个易患NTD的小鼠突变系，在这些突变系中，NTD的发生对叶酸补充敏感。叶酸代谢是S腺苷蛋氨酸的来源，它是甲基化核酸、蛋白质和脂肪的主要甲基供体。提供甲基供体被认为是叶酸补充对神经形成起到有益作用的主要途径。我们将使用应用于小鼠和人类患者材料的尖端和新兴技术来询问基因组范围的甲基化和染色质重塑相互作用，与个体基因相关，以检查表观遗传对转录组和表型结果的影响。这一建议测试了一种假设，即在调节DNA和染色质甲基化的产前补充背景下，DNA和染色质的表观遗传修饰将影响可识别的基因表达模式，从而以一种可以基于个体基因预测的方式促进或损害神经形成。此外，我们假设，某些模式不仅在发育中的神经管中明显，而且在外周血中也明显，因此在临床环境下评估风险和最佳NTD预防将是有用的。我们预测，在子宫中获得的一些DNA和染色质甲基化特征将在出生后持续存在，无论出生后是否继续补充。最后，我们预计在老鼠身上发现的DNA甲基化模式也将出现在受NTD影响的人类患者中--至少在途径水平上--如果不是单个基因的话。

DESCRIPTION (provided by applicant): Modifications of DNA and chromatin impact the accessibility of the genetic code to the biological machinery of the cell. Relating epigenomic changes to neurodevelopmental disorders has been challenging. One obstacle is the need to study the relevant tissues at an appropriate stage of the disease process, while another is the difficulty of understanding the relationship of nucleotide and chromatin modifications to complex genetic disorders in which multiple loci interactions underlie expression of the disease. We propose to take advantage of a disorder, neural tube defects (NTDs), in which the existing mouse models closely parallel the human disease and in which several lines of evidence indicate a strong influence in both mouse and man of epigenetic modifications regulating disease expression. We will combine proof of principle studies in the mouse with investigations of human NTD cohorts to examine the relationship between DNA/chromatin methylation and the expressivity of NTDs in genetically susceptible individuals. The study of epigenetic events contributing to NTDs has multiple distinct advantages over epigenomic investigation of other human diseases, as more than 200 genes are implicated in NTDs by human or animal studies. These provide critical clues to molecular pathways important for normal neurulation. Supporting the existing clinical data, we discovered several NTD-prone mouse mutant lines in which NTD occurrence is sensitive to folic acid supplementation. Folate metabolism is the source of al S-adenosyl methoinine (SAM), which is the primary methyl donor for methylating nucleic acids, proteins and lipids. Providing methyl donors is thought to be a major route through which folate supplementation exerts its beneficial effects on neurulation. We will use cutting edge and emerging technologies applied to mouse and human patient material to interrogate genome wide methylation and chromatin remodeling interactions, correlated with individual genotype, to examine epigenetic effects on the transcriptome and on phenotypic outcome. This proposal tests the hypothesis that epigenetic modifications in DNA and chromatin in the setting of prenatal supplementation that modulates DNA and chromatin methylation will impact a recognizable pattern of gene expression to either favor or impair neurulation in a manner that can be predicted based on individual genotype. Moreover, we hypothesize that certain patterns will be evident not only in the developing neural tube but also in the peripheral blood and so will be useful in evaluating risk and optimal NTD prevention in a clinical setting. We predict that some DNA and chromatin methylation signatures acquired in utero wil persist postnatally, regardless of whether supplementation continues after birth. Finally, we expect that DNA methylation patterns found in mouse will be present as well-at least at the level of pathways if not individual genes-in human patients affected by an NTD.