Epigenome Interactions in Complex Neurogenetic Disorders

复杂神经遗传疾病中的表观基因组相互作用

基本信息

批准号：
8181076
负责人：
Christopher Edward Mason
金额：
$ 118.67万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8181076
关键词：
Adult Affect Age Algorithms Alzheimer&apos s Disease Animals Autistic Disorder Betaine Binding Biological Birth Blood Cancer Biology Carbon Cells Chromatin Clinical Clinical Data Complex DNA DNA Methylation DNA Modification Process Data Dependence Detection Development Diet Disease Embryo Emerging Technologies Employee Strikes Ensure Epigenetic Process Event Failure Family Folate Folic Acid Food Supply Fortified Food Gene Expression Gene Expression Profile Genes Genetic Genetic Code Genetic Models Genetic Transcription Genome Genomics Genotype Hereditary Disease Histones Human Human Genetics Individual Infant Intake Intervention Investigation Knockout Mice Life Lipids Long Interspersed Nucleotide Elements Machine Learning Major Depressive Disorder Mediating Metabolic Metabolic Pathway Metabolism Methionine Methylation Modification Molecular Mus Mutant Strains Mice Mutation Neonatal Neural Tube Closure Neural Tube Defects Neural tube Neurodevelopmental Disorder Newborn Infant Nucleic Acids Nucleotides Outcome Partner in relationship Pathway interactions Patients Pattern Phenotype Population Pregnant Women Prevention Prevention strategy Process Proteins RNA Sequences RNA Splicing Recommendation Risk Role Route Sampling Signal Transduction Source Spinal Dysraphism Spottings Staging Supplementation Surveys Testing Tissues Translating Variant Work arm base bisulfite chromatin immunoprecipitation chromatin modification chromatin remodeling cohort embryo tissue epigenetic variation epigenomics folate-binding protein folic acid metabolism fortification genome-wide human disease in utero innovation loss of function man mouse model neonate neurogenetics peripheral blood prenatal promoter receptor response standard of care stem

项目摘要

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. PUBLIC HEALTH RELEVANCE: There is a critical need to identify patterns of human genetic--modified by epigenetic--variation that will allow individual risks to be accurately assessed. This would enable NTD prevention strategies to be optimized for each family, rather than basing recommendations on whole populations. With our food supply now fortified, folic acid has become the most widely administered medicinal agent in the US today. Therefore, this study will also have broad relevance to human disorders in which folate intake has an implicated role, including major depression, autism, Alzheimer's disease, among others.

描述（由申请人提供）：DNA和染色质的修饰会影响遗传代码的可及性对细胞的生物机械的可及性。将表观基因组变化与神经发育障碍有关的变化一直具有挑战性。一个障碍是需要在疾病过程的适当阶段研究相关组织，而另一个障碍是很难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该疾病表达的基础。我们建议利用疾病，神经管缺陷（NTD），其中现有小鼠模型与人类疾病紧密平行，其中几种证据表明对调节疾病表达的小鼠和表观遗传修饰的人都有强大的影响。我们将在小鼠中的原理研究证明与人类NTD队列的研究相结合，以检查DNA/染色质甲基化与遗传易感个体中NTD的表达之间的关系。与其他人类疾病的表观基因组研究相比，对促成NTD的表观遗传事件的研究具有多个不同的优势，因为人类或动物研究与NTD有关200多个基因。这些为分子途径提供了关键的线索，对正常神经素质很重要。支持现有的临床数据，我们发现了几条NTD易于的小鼠突变型线，其中NTD发生对补充叶酸敏感。叶酸代谢是Al s-腺苷甲氧氨酸（SAM）的来源，它是用于甲基化核酸，蛋白质和脂质的主要甲基供体。提供甲基供体被认为是一条主要途径，叶酸补充对神经造成的有益作用。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审查基因组广泛的甲基化和与个体基因型相关的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作用。该提案检验了以下假设：在补充产前补充的情况下，DNA和染色质的表观遗传修饰调节DNA和染色质甲基化将影响基因表达的可识别模式，以基于个体基因型的方式以可以预测的方式受到损害神经肿瘤。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很明显，因此在评估临床环境中的风险和最佳NTD预防方面非常有用。我们预测，无论补充出生后是否继续持续，在子宫内获得的一些DNA和染色质甲基化特征会持续下去。最后，我们预计，如果不是受NTD影响的单个基因患者，则在小鼠中发现的DNA甲基化模式至少在途径水平上存在。公共卫生相关性：通过表观遗传学对人类遗传的模式进行迫切需要，这将使个人风险准确评估。这将使NTD预防策略能够为每个家庭进行优化，而不是基于整个人群的建议。随着我们的粮食供应现已加强，叶酸已成为当今美国管理最广泛的药物。因此，这项研究还将与人类疾病具有广泛的相关性，其中叶酸摄入具有牵连的作用，包括重大抑郁症，自闭症，阿尔茨海默氏病等。