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

• 批准号: 8769495
• 负责人: Andrew Ellis Jaffe
• 金额: $ 36.6万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769495
• 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; Gene Expression Regulation; 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; brain tissue; cell type; clinical risk; critical period; emerging adult; epigenome; fetal; follow-up; frontal lobe; neuropsychiatry; next generation sequencing; novel; public health relevance; risk variant; young adult

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（DNA m）是基因表达表观遗传调节的重要组成部分，负责协调从胎儿到青春期甚至更长时间的组织分化和发育。在人类大脑中，基因表达在这一重要的发育时间范围内是极其动态的（Colantuoni 2011），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起着核心作用（Weinberger 2011）。我们假设，偏离基本DNAm的发展轨迹，无论是通过遗传因素和/或环境的侮辱，可能会干扰这些精心协调的基因表达模式。 由于精神分裂症的风险建立的表观遗传机制必须提前的疾病的发展，和大部分的变异性位点特异性DNA发生在胎儿期通过青年成年，我们建议全基因组亚硫酸氢盐测序（WGBS）在死后的脑组织从“正常”的个人范围从第一个三个月到25岁。这种对60个大脑样本的下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鉴定其中相邻胞嘧啶处的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与相同大脑样本的现有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中的基因表达。 对生命最初30年中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一个重大障碍。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，定义了精神分裂症中可能出错的多维“正常”模式。