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

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（申请人提供）：通过ENCODE项目的努力，在绘制基因组功能单元以及表观基因组图谱方面取得了很大进展，这些工作主要在细胞系和外周组织中进行。我们的 PsychENCODE 项目的目标是构建与精神分裂症 (SCZ)、人类神经元和神经胶质细胞特定相关的组织中多个重要染色质修饰的详细图谱，并随后评估其中几个标记与 SCZ 已知遗传风险因素的关系。我们将首先在有限数量的样本中广泛调查两个大脑区域（前额叶皮层和前扣带皮层）中的一系列重要染色质标记，以提供染色质标记的大脑和神经元特异性图。然后，我们将深入研究大量死后人类大脑样本中的一个区域，即前额皮质，以及重要的启动子和增强子标记。具体来说，我们将首先使用荧光激活细胞分选，然后进行 ChIP-Seq 绘制皮质组织匀浆以及正常成人大脑 (n=20) 细胞核中神经元和非神经元染色质中细胞类型特异性转录组和表观基因组成分的图谱。。其次，我们将绘制 328 例 SCZ 病例和 315 例对照的前额皮质神经元染色质中的启动子 (H3K4me3) 和增强子 (H3K27ac) 标记。我们将把全基因组 SNP、CNV 和大脑 mRNA 表达与神经元 ChIP-seq 启动子和增强子标记相整合，以使用各种分析策略来识别新的 SCZ 基因，包括构建加权相互作用和因果概率 SCZ 网络，以识别潜在的关键驱动因素和子网络SCZ。最后，我们将使用染色体构象捕获来绘制远端增强子元件，并研究药物混淆对绘制结果的作用。我们的 PsychENCODE 项目将应用创新技术和分析策略，包括细胞类型特异性表观基因组图谱、染色体构象捕获、反卷积图谱和因果概率网络分析的构建。所有数据将通过 Sage Bionetworks Synapse 平台提供给研究界。迫切需要了解人脑中的表观遗传景观，特别是神经元和神经胶质细胞中的表观遗传景观，并将这些信息与人类 SCZ 遗传学相整合。我们已经聚集了关键的关键人员、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图谱，并开始解开 SCZ 生物学。