Epigenome Interactions in Complex Neurogenetic Disorders

描述（由申请人提供）：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一个挑战。一个障碍是需要在疾病过程的适当阶段研究相关组织，而另一个障碍是难以理解核苷酸和染色质修饰与复杂遗传疾病的关系，其中多个基因座相互作用是疾病表达的基础。我们建议利用一种疾病，神经管缺陷（NTDs），其中现有的小鼠模型与人类疾病密切平行，并且其中几条证据表明表观遗传修饰调节疾病表达对小鼠和人都有很强的影响。我们将结合联合收割机在小鼠中进行的原理验证研究和对人类NTD队列的研究，以检查遗传易感个体中DNA/染色质甲基化与NTD表达率之间的关系。 与其他人类疾病的表观基因组研究相比，对导致NTD的表观遗传事件的研究具有多个明显的优势，因为通过人类或动物研究，超过200个基因与NTD有关。这些为正常神经形成的重要分子通路提供了关键线索。支持现有的临床数据，我们发现了几个NTD倾向的小鼠突变株，其中NTD的发生是敏感的叶酸补充。叶酸代谢是α 1-S-腺苷甲硫氨酸（SAM）的来源，SAM是核酸、蛋白质和脂质甲基化的主要甲基供体。提供甲基供体被认为是叶酸补充剂对神经形成发挥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与个体基因型相关的全基因组甲基化和染色质重塑相互作用，以检查对转录组和表型结果的表观遗传效应。 该提案测试了以下假设：在产前补充剂的情况下，DNA和染色质的表观遗传修饰调节DNA和染色质甲基化，这将影响可识别的基因表达模式，从而以可基于个体基因型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，而且在外周血中也是明显的，因此在临床环境中评估风险和最佳NTD预防将是有用的。我们预测，无论出生后是否继续补充，子宫内获得的一些DNA和染色质甲基化特征将持续存在。最后，我们期望在小鼠中发现的DNA甲基化模式也将存在于受NTD影响的人类患者中-至少在通路水平上，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.