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具有挑战性。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，在这些疾病中，多位点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非常相似，并且有几条证据表明，在小鼠和人类中，调节疾病表达的表观遗传修饰都有很强的影响。我们将把小鼠的原理证明研究与人类NTD队列的研究结合起来，研究DNA/染色质甲基化与遗传易感个体中NTD的表达性之间的关系。与其他人类疾病的表观基因组研究相比，对导致被忽视热带病的表观遗传事件的研究具有多种明显的优势，因为通过人类或动物研究，有200多个基因与被忽视热带病有关。这些为正常神经发育的重要分子通路提供了关键线索。支持现有的临床数据，我们发现了几种NTD易发小鼠突变系，其中NTD的发生对叶酸补充敏感。叶酸代谢是s -腺苷甲氨酸（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发挥其对神经的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，以检查表观遗传对转录组和表型结果的影响。这一建议验证了一种假设，即在产前补充DNA和染色质甲基化的情况下，DNA和染色质的表观遗传修饰将影响一种可识别的基因表达模式，以一种可以基于个体基因型预测的方式促进或损害神经发育。此外，我们假设某些模式不仅在发育中的神经管中很明显，而且在外周血中也很明显，因此将有助于评估临床环境中的风险和最佳的NTD预防。我们预测，在子宫内获得的一些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，我们期望在小鼠中发现的DNA甲基化模式也会出现在NTD患者中，至少在途径水平上，如果不是单个基因。

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.