Linking Psychiatric Genetics to Cell-Type Specific Enhancer Function

将精神病遗传学与细胞类型特异性增强子功能联系起来

基本信息

批准号：
10400937
负责人：
Axel Visel
金额：
$ 71.91万
依托单位：
UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400937
关键词：
Affect Biological Assay Brain Brain Mapping Brain region Catalogs Cells ChIP-seq Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Code Collection DNA Data Data Set Development Disease Distant Embryo Engineering Enhancers Etiology Funding Gene Expression Gene Expression Alteration Gene Transfer Techniques Genetic Genetic Enhancer Element Genetic Transcription Genetic study Genome Gold Histologic Human Human Genetics Human Genome Individual Label Lead Link Linkage Disequilibrium Maps Mediating Mental disorders Methods Molecular Mus Nervous System Physiology Neuroanatomy Neurobiology Neurons Pattern Phenotype Population Proteins Reporting Resolution Resources Risk Scheme Series Site Specificity Structure Testing Time Tissues Transgenic Mice United States National Institutes of Health Untranslated RNA Validation Variant Work base brain tissue cell type cohort comparative disorder risk epigenomics experimental study follow-up functional genomics genome sequencing genome wide association study improved in vivo in vivo evaluation insight member neuropsychiatric disorder novel novel strategies predictive test prenatal psychogenetics risk variant single-cell RNA sequencing therapy development transcriptome whole genome

项目摘要

PROJECT SUMMARY Genome-wide association studies (GWAS) provide robust statistical evidence linking individual sequence variants to increased risk of disease. However, the majority of GWAS-identified risk variants identified to date, including those for psychiatric disorders, do not affect protein-coding sequence but instead map to noncoding DNA. GWAS alone yield little direct insight into the mechanisms by which these variants confer increased risk. It is widely assumed that many affect the function of distant-acting transcriptional enhancers, but the historically poor annotation of noncoding functional sequences in the human genome has rendered their interpretation challenging. Over the past decade, our lab and others made substantial progress toward identifying enhancers in the genome at scale. For example, our group has used ChIP-seq from mouse and human brain tissues to identify initial collections of developmentally active brain enhancers. Furthermore, as members of the ENCODE consortium, we generated the first high-resolution time series mapping the brain chromatin landscape throughout mouse prenatal development. These resources, along with complementary data from NIH-funded consortia, are now available to aid in the interpretation of GWAS results. Here we propose to bridge the current gap between noncoding GWAS findings and mechanistic understanding of psychiatric disorder etiology. We will couple extensive pre-existing epigenomic resources to cutting-edge mouse engineering and single cell-resolution transcriptome analyses in order to understand how enhancer variants contribute to psychiatric disease risk. Specifically we will: 1) Perform an integrative analysis of psychiatric disorder GWAS results and epigenomically predicted brain enhancers to identify regulatory sequences that harbor disease-associated variants and prioritize them for functional validation, 2) Use high-throughput mouse transgenic assays to validate predicted enhancers in vivo and determine the exact brain regions in which they are active, 3) Use single cell RNA-sequencing of transgenic mice to determine the exact cell type(s) in which a brain enhancer functions, and 4) Use these in vivo functional genomic methods to uncover whether and how disease-associated sequence variants impact the cell type-specific activity of each enhancer. As whole genome sequencing of psychiatric disease cohorts continues to progress, we will also assess variants from those studies. In combination, our work will uncover how noncoding disease-associated variants alter enhancer function in vivo, link noncoding GWAS findings to specific cell types, and provide a unique panel of well-characterized enhancers that can be used to label discrete neuronal cell populations for further downstream characterization. The results will substantially improve our mechanistic understanding of how noncoding sequence changes contribute to mental illness and provide entry points for potential downstream therapies.

项目摘要全基因组关联研究（GWAS）提供了可靠的统计证据，与个人序列联系起来变体增加了疾病的风险。但是，迄今为止确定的大多数GWAS识别风险变体，包括精神疾病的人，不要影响蛋白质编码顺序，而是映射到非编码脱氧核糖核酸。仅GWAS几乎没有直接深入了解这些变体赋予风险增加的机制。人们普遍认为，许多人都会影响遥远的转录增强剂的功能，但是历史上，人类基因组中非编码功能序列的注释不良已使他们解释具有挑战性。在过去的十年中，我们的实验室和其他人在根据大规模识别基因组中的增强子。例如，我们的小组使用了鼠标和人脑组织以鉴定发育活跃的脑增强剂的初始收集。此外，AS 编码财团的成员，我们生成了第一个高分辨率时间序列映射大脑整个小鼠产前发育中的染色质景观。这些资源以及互补的 NIH资助的财团的数据现在可以帮助解释GWAS结果。我们在这里提议弥合非编码GWAS发现与机械理解之间的当前差距精神疾病病因。我们将将广泛存在的表观基因组资源与尖端的小鼠工程和单细胞分辨率转录组分析，以便了解增强剂变体如何促进精神病风险。具体我们将：1）执行精神障碍GWAS结果和表观遗传学预测的脑增强子的综合分析确定具有疾病相关的变体的调节序列，并将其优先级以进行功能验证，2）使用高通量小鼠转基因测定法以在体内验证预测的增强剂确定其活性的确切大脑区域，3）使用转基因的单细胞RNA测序小鼠确定脑增强子功能的确切细胞类型，4）在体内使用这些细胞类型功能性基因组方法，以发现以及与疾病相关的序列变体的影响以及如何影响每个增强子的细胞类型特异性活性。作为精神疾病队列的整个基因组测序继续进步，我们还将评估这些研究的变体。结合在一起，我们的工作将揭开非编码疾病相关的变体如何改变体内增强子功能，将非编码GWAS的发现与特定的细胞类型，并提供一个独特的特征良好增强剂的面板，可用于标记离散的神经元细胞群，以进一步的下游表征。结果将大大提高我们对非编码序列变化如何有助于精神疾病和提供潜在下游疗法的入口点。