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Establishing comprehensive and quantitative maps of DNA methylation in the develo

建立开发中 DNA 甲基化的全面定量图谱

基本信息

批准号：
9039200
负责人：
Andrew Ellis Jaffe
金额：
$ 9.25万
依托单位：
LIEBER INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039200
关键词：
Adolescence Adult Affect Age Age-Years Aging Algorithms Biological Brain Brain Diseases Brain region Cells Communities Cytosine DNA DNA Methylation Data Data Set Development Dinucleoside Phosphates Disease Environmental Risk Factor Epigenetic Process Fetal Development Fetus First Pregnancy Trimester Functional disorder Future Gene Expression Gene Expression Profile Genes Genetic Genetic Variation Genome Grant Human Individual Knowledge Life Link Longevity Maps Measures Mental disorders Methylation Microarray Analysis Modification Molecular Biology Motor Neurodevelopmental Disorder Neurons Patients Pattern Play Predisposition Prefrontal Cortex Process RNA Sequences Relative (related person)Research Resolution Risk Role Sampling Schizophrenia Short-Term Memory Site Sorting - Cell Movement Staging Techniques Testing Time Tissue Differentiation Tissues Transcript Work age related base bisulfite sequencing brain tissue cell type clinical risk critical period emerging adult epigenetic regulation epigenome fetal follow-up frontal lobe neuropsychiatry next generation sequencing novel public health relevance risk variant transcriptome sequencing young adult

项目摘要

DESCRIPTION (provided by applicant): DNA methylation (DNAm) is a crucial component of the epigenetic regulation of gene expression, orchestrating tissue differentiation and development from fetus to adolescence, and likely beyond. In the human brain, gene expression is extremely dynamic through this important time frame of development (Colantuoni 2011) and dysregulation of the early maturational stages of the brain plays a central role in neurodevelopmental disorders such as schizophrenia (Weinberger 2011). We hypothesize that deviations from essential DNAm developmental trajectories, either through genetic factors and/or environmental insults, could interfere with these carefully coordinated patterns of gene expression. Since schizophrenia risk established by epigenetic mechanisms must pre-date the development of the disorder, and the majority of the variability in site-specific DNAm occurs during fetal life through young adulthood, we propose whole genome bisulfite sequencing (WGBS) in post-mortem brain tissue from "normal" individuals ranging from the late first trimester through 25 years of age. This next-generation sequencing approach on 60 brain samples can measure DNAm levels at every cytosine dinucleotide (including non-CpG contexts) in each genome, whereas existing DNAm microarray technologies only measure DNAm levels at a fraction of the total CpGs. This magnified resolution permits identifying regions where DNAm levels at adjacent cytosines are associated with development and aging (differentially methylated regions, or "DMRs"). We can then integrate these DMRs with existing RNA sequencing data on the same brain samples to identify which DMRs are functionally involved in regulating gene expression in the developing human brain. The lack of knowledge about the normal patterns of DNA methylation during the first three decades of life is a significant hindrance towards understanding how genetic variation interacts with environmental factors in altering risk for illness. This integrative approach, combining whole-genome bisulfite sequencing data and RNA sequencing data, prioritizes regions of epigenome imperative to development, defining multidimensional patterns of "normal" that are likely go awry in schizophrenia.

描述（由申请人提供）：DNA 甲基化 (DNAm) 是基因表达表观遗传调控的重要组成部分，协调组织分化和从胎儿到青春期甚至更远的发育。在人脑中，基因表达在这一重要的发育时间范围内极其动态（Colantuoni 2011），并且大脑早期成熟阶段的失调在精神分裂症等神经发育障碍中发挥着核心作用（Weinberger 2011）。我们假设，由于遗传因素和/或环境损害而偏离基本 DNAm 发育轨迹，可能会干扰这些精心协调的基因表达模式。由于表观遗传机制确定的精神分裂症风险必须早于疾病的发展，并且位点特异性 DNAm 的大部分变异发生在胎儿期到成年早期，因此我们建议对从妊娠早期晚期到 25 岁的“正常”个体的死后脑组织进行全基因组亚硫酸氢盐测序 (WGBS)。这种针对 60 个大脑样本的新一代测序方法可以测量每个基因组中每个胞嘧啶二核苷酸（包括非 CpG 背景）的 DNAm 水平，而现有的 DNAm 微阵列技术只能测量总 CpG 的一小部分的 DNAm 水平。这种放大的分辨率允许识别相邻胞嘧啶的 DNAm 水平与发育和衰老相关的区域（差异甲基化区域，或“DMR”）。然后，我们可以将这些 DMR 与同一大脑样本的现有 RNA 测序数据整合，以确定哪些 DMR 在功能上参与调节发育中的人类大脑的基因表达。对生命前三十年 DNA 甲基化的正常模式缺乏了解，是理解遗传变异如何与环境因素相互作用以改变疾病风险的重大障碍。这种综合方法结合了全基因组亚硫酸氢盐测序数据和 RNA 测序数据，优先考虑对发育至关重要的表观基因组区域，定义了在精神分裂症中可能出错的“正常”多维模式。