Cis-Regulatory Epigenome Mappings in Schizophrenia

精神分裂症的顺式调控表观基因组图谱

基本信息

批准号：
8677266
负责人：
Schahram Akbarian
金额：
$ 154.01万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2014-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8677266
关键词：
Adult Age Anterior Antibodies Antipsychotic Agents Architecture Autopsy Biology Brain Brain region Cell Line Cell Nucleus Cerebral cortex ChIP-seq Chromatin Chromosome Mapping Chromosomes Chronic Clozapine Communities Complex Computer Simulation DNA Data Data Set Diagnosis Disease Distal Enhancer Elements Enhancers Epigenetic Process Fluorescence-Activated Cell Sorting Gender Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Genetic Risk Genetic Transcription Genome Genomics Genotype Goals Greek Haloperidol Human Human Resources Lysine Macaca Maps Methods Modeling Molecular Conformation Monkeys National Institute of Mental Health Neurobiology Neuroglia Neurons Nuclear RNA Peripheral Pharmaceutical Preparations Policies Positioning Attribute Prefrontal Cortex Quantitative Trait Loci RNA Sequences Research Resources Risk Role Sampling Schizophrenia Series Signal Transduction Site Specificity Superior temporal gyrus Surveys Synapses Techniques Tissues United States Variant Weight Work brain tissue case control cell type chromatin modification cingulate cortex cohort cost data sharing design epigenome epigenomics exome follow-up frontal lobe genetic risk factor genome wide association study genome-wide histone modification innovation mRNA Expression novel promoter public health relevance rare variant transcriptome sequencing

Adult Age Anterior Antibodies Antipsychotic Agents Architecture Autopsy Biology Brain Brain region Cell Line Cell Nucleus Cerebral cortex ChIP-seq Chromatin Chromosome Mapping Chromosomes Chronic Clozapine Communities Complex Computer Simulation DNA Data Data Set Diagnosis Disease Distal Enhancer Elements Enhancers Epigenetic Process Fluorescence-Activated Cell Sorting Gender Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Genetic Risk Genetic Transcription Genome Genomics Genotype Goals Greek Haloperidol Human Human Resources Lysine Macaca Maps Methods Modeling Molecular Conformation Monkeys National Institute of Mental Health Neurobiology Neuroglia Neurons Nuclear RNA Peripheral Pharmaceutical Preparations Policies Positioning Attribute Prefrontal Cortex Quantitative Trait Loci RNA Sequences Research Resources Risk Role Sampling Schizophrenia Series Signal Transduction Site Specificity Superior temporal gyrus Surveys Synapses Techniques Tissues United States Variant Weight Work brain tissue case control cell type chromatin modification cingulate cortex cohort cost data sharing design epigenome epigenomics exome follow-up frontal lobe genetic risk factor genome wide association study genome-wide histone modification innovation mRNA Expression novel promoter public health relevance rare variant transcriptome sequencing

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项目摘要

DESCRIPTION (provided by applicant): Great progress has been made in mapping functional units of the genome as well as the epigenome through the efforts of the ENCODE project, such work has mainly been carried out in cell lines and peripheral tissues. The goal of our PsychENCODE project is to construct detailed maps for multiple important chromatin modifications in a tissue of specific relevance to schizophrenia (SCZ), human neurons and glia, and subsequently assess the relationship of several of these marks to known genetic risk factors for SCZ. We will first broadly survey a series of important chromatin marks in two brain regions, the pre-frontal cortex and anterior cingulate cortex, in limited number of samples to provide brain and neuronal specific maps of the chromatin marks. We will then focus deeply on a single region, the pre-frontal cortex, and on an important promoter and enhancer mark, in a large sample of post-mortem human brain samples. Specifically, we will first, map cell-type specific transcriptome and epigenome components in cortical tissue homogenates and in neuronal and non-neuronal chromatin in nuclei from normal human adult brain (n=20) using fluorescence- activated cell sorting followed by ChIP-Seq. Second, we will map promoter (H3K4me3) and enhancer (H3K27ac) marks in neuronal chromatin of the prefrontal cortex of 328 cases with SCZ, and 315 controls. We will integrate genome-wide SNP, CNV and brain mRNA expression with the neuronal ChIP-seq promoter and enhancer marks to identify novel SCZ genes using a variety of analytic strategies including constructing weighted interaction and causal probabilistic SCZ networks to identify key drivers and subnetworks underlying SCZ. Finally, we will map distal enhancer elements using chromosome conformation capture and investigate the role of medication confounds on mapping results. Our PsychENCODE project will apply innovative techniques and analytic strategies including cell-type specific epigenome mapping, chromosome conformation capture, deconvolution mapping and construction of causal probabilistic network analyses. All data will be made available to the research community through the Sage Bionetworks Synapse Platform. There is a deep need to understand the epigenetic landscape in the human brain, and in particular in neurons and glia and to integrate this information with human SCZ genetics. We have assembled the critical key personnel, sample resources, technological know-how, and analytic strategies to be able to provide both useful maps for the field, as well as begin to unravel SCZ biology.

描述（由申请人提供）：通过编码项目的努力，在映射基因组以及表观基因组的功能单元中取得了巨大进展，此类工作主要是在细胞系和外围组织中进行的。我们的Psychencode项目的目的是在与精神分裂症（SCZ），人类神经元和神经胶质的特定相关组织中构建多个重要染色质修饰的详细图，并随后评估了这些标记中的几个标记与已知的SCZ遗传风险因素的关系。我们将首先在两个大脑区域（额额皮层和前扣带回皮层）中广泛调查一系列重要的染色质标记，以有限数量的样品提供染色质标记的大脑和神经元特定图。然后，在大量的验尸和增强子标记中，我们将深入关注单个区域，额外的额叶和增强子标记。具体而言，我们将首先，使用正常人大脑（n = 20）的核中皮质组织匀浆中的细胞类型特异性转录组和表观基因组成分，以及使用荧光激活的细胞排序，然后由chip-seq进行荧光激活的细胞分类。其次，我们将绘制启动子（H3K4me3）和增强子（H3K27AC）标记的额叶染色质的328例SCZ病例和315个对照组的神经元染色质。我们将使用各种分析策略将全基因组SNP，CNV和脑mRNA表达与神经元芯片启动子和增强子标记整合在一起，以鉴定新型SCZ基因，包括构建加权相互作用和构建因果概率SCZ网络，以识别SCZ的基础SCZ和子网络。最后，我们将使用染色体构象捕获远端增强子元素绘制远端增强子元素，并研究药物混淆在映射结果中的作用。我们的Psychencode项目将采用创新技术和分析策略，包括细胞类型的特定表观基因组映射，染色体构象捕获，反卷积映射和因果概率网络分析的构建。所有数据将通过Sage Bionetworks Synapse平台向研究社区提供。需要深入了解人脑中的表观遗传景观，尤其是在神经元和神经胶质中，并将这些信息与人类SCZ遗传学相结合。我们已经组建了关键的关键人员，样本资源，技术知识和分析策略，以便能够为该领域提供有用的地图，并开始解开SCZ生物学。