Single cell transcriptional and epigenomic atlas of the macaque brain across the lifespan

猕猴整个生命周期的单细胞转录和表观基因组图谱

基本信息

批准号：
10248566
负责人：
MICHAEL L PLATT
金额：
$ 160.81万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-17 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248566
关键词：
ATAC-seq Adult Age Anatomy Animal Model Animals Area Atlases Biological Models Brain Brain Diseases Brain region Cell Nucleus Cell physiology Cells Cercopithecidae Chromatin Communities Complex Data Data Set Development Disease Epigenetic Process Etiology Exhibits Female Freezing Future Gene Expression Profiling Genes Genetic Transcription Human Individual Intervention Island Longevity Macaca Macaca mulatta Maps Methods Molecular Molecular Analysis Molecular Profiling Mus Neurobiology Neurodevelopmental Disorder Neurophysiology - biologic function Organ Population Population Research Primates Protocols documentation Puerto Rico Research Research Personnel Resolution Resources Sample Size Sampling Social Behavior Structure Study models Surveys System Variant biobank brain cell brain tissue cell type cognitive function combinatorial computational pipelines cost epigenetic profiling epigenome epigenomics experimental study fly gene expression database indexing male neurobehavioral neuropsychiatric disorder new technology nonhuman primate novel sample collection sex social group transcriptome transcriptome sequencing

项目摘要

ABSTRACT / SUMMARY New technologies are enabling molecular profiling of single brain cells at remarkable throughput. However, these new methods have yet to be extensively applied to the brains of model organisms that bridge the evolutionary distance between mouse and human, including the most common nonhuman primate model system - the rhesus macaque. Here we propose to generate an anatomically resolved, single cell atlas of the epigenome (5.5 million cells) and transcriptome (11 million cells) of the rhesus macaque brain. We will apply two methods, recently developed in our labs, that rely on “combinatorial indexing” to cost-effectively profile the epigenomes (sci-ATAC-seq) and transcriptomes (sci-RNA-seq) of large numbers of cells or nuclei. As our first aim, we will generate high resolution, single cell epigenetic and transcriptional atlases of one male and one female rhesus macaque brain. Specifically, we will profile chromatin accessibility in 750,000 nuclei (sci-ATAC- seq) and transcription in 1,500,000 nuclei (sci-RNA-seq) from each of two macaque brains (for a total of 4.5 million cells). These will be obtained from 25 anatomically dissected brain regions (30,000 sci-ATAC-seq and 60,000 sci-RNA-seq profiles per region per brain). As our second aim, we will extend these atlases to span the primate lifespan. Specifically, we will perform single cell epigenetic and transcriptional profiling of the brains of 50 additional rhesus macaques (25 regions per brain; 3,200 sci-ATAC-seq and 6,400 sci-RNA-seq profiles per individual/region, for a total of 12 million molecularly profiled cells). This large sample size will allow us to characterize natural variation in chromatin accessibility and transcription within each cell type, between individuals, sexes, and across the natural lifespan of rhesus macaques. At 16.5 million cells, our rhesus macaque brain atlas will comprise the largest transcriptional and epigenomic single cell dataset of any primate organ to date. Our data will be rapidly shared with BICCN and the broader community. We anticipate it will be an essential resource, complementary to other efforts, for identifying the distribution and function of key cell types across the primate brain, allowing for the development of cell type- and region-specific molecular interventions that will help us understand brain function and the etiology, and potentially the treatment, of brain disorders.

摘要/总结新技术正在以惊人的通量对单个脑细胞进行分子分析。这些新方法尚未广泛应用于模型生物的大脑，以桥接小鼠和人类之间的进化距离，包括最常见的非人类灵长类动物模型系统 - 恒河猴在这里，我们建议生成一个解剖学解析的单细胞图谱。我们将应用恒河猴大脑的表观基因组（550 万个细胞）和转录组（1100 万个细胞）。我们的实验室最近开发了两种方法，它们依靠“组合索引”来经济有效地分析大量细胞或细胞核的表观基因组 (sci-ATAC-seq) 和转录组 (sci-RNA-seq) 作为我们的第一个。目标是，我们将生成一名男性和一名男性的高分辨率单细胞表观遗传和转录图谱具体来说，我们将分析 750,000 个细胞核中的染色质可及性 (sci-ATAC- seq）和来自两个猕猴大脑各 1,500,000 个细胞核的转录（sci-RNA-seq）（总共 4.5 百万个细胞）。这些将从 25 个解剖学解剖的大脑区域获得（30,000 个 sci-ATAC-seq 和每个大脑每个区域 60,000 个 sci-RNA-seq 配置文件）作为我们的第二个目标，我们将扩展这些图谱以跨越整个区域。具体来说，我们将对灵长类动物的大脑进行单细胞表观遗传和转录分析。另外 50 只恒河猴（每个大脑 25 个区域；每个大脑 3,200 个 sci-ATAC-seq 和 6,400 个 sci-RNA-seq 配置文件）个人/区域，总共 1200 万个分子分析细胞）。如此大的样本量将使我们能够表征每种细胞类型内染色质可及性和转录的自然变化恒河猴的个体、性别和自然寿命我们的恒河猴有 1650 万个细胞。猕猴大脑图谱将包含灵长类动物中最大的转录和表观基因组单细胞数据集迄今为止，我们的数据将迅速与 BICCN 和更广泛的社区共享。一种重要资源，可补充其他工作，用于确定关键细胞的分布和功能灵长类动物大脑中的类型，允许细胞类型和区域特异性分子的发育干预措施将帮助我们了解大脑功能和病因，以及潜在的治疗方法失调。