Single-cell Mapping Center for Human Regulatory Elements and Gene Activity

项目摘要/摘要 人类细胞中DNA调控元件和基因表达的全面全基因组图谱 对了解基因组变异如何影响人类健康和疾病至关重要。自监管机构 DNA元素是特殊的细胞类型、组织和疾病状态特定的，是这些元素的全面目录 这些要素一直很难实现。该IGVF测绘中心的总体使命是创建一个高- 人类调节元件和基因的高质量、开放获取和单细胞分辨率参考图谱 在人类发育过程中的免疫细胞、健康成人的跨器官系统和组织中的表达 来自不同的免疫相关疾病。我们的测绘中心将利用：(I)我们在开发 可扩展且经济高效的单细胞表观基因组和多基因组技术，可同时绘制开放图谱 每个组织中的染色质位置、基因表达、细胞内和细胞表面蛋白以及克隆性谱系追踪 样本，(Ii)我们先前的技术改进和这些方法在人类初级组织中的应用， 和(Iii)我们先前存在的人体组织生物库，由500多个人类个体的样本组成，20 器官系统和15种疾病，同意不受限制地访问、基因组测序和数据 分享。在具体目标1中，我们将与IGVF联盟密切合作，为数据制定跨中心计划 样本获取和共享的生成、分析和有效协调。在具体目标2中，我们将 生成免疫细胞类型(和非免疫细胞类型，由 IGVF)在生命早期发育、健康衰老和整个人体器官系统。在具体目标3中， 我们将从患者的原始组织中建立一份免疫细胞类型的单细胞多组图谱 自身免疫、癌症、神经退行性疾病和感染。在具体目标4中，我们将分析监管 从线粒体谱系推测克隆分化轨迹中的位置和基因表达 追踪、开发和维护每种数据类型和组织样本的综合参考图 研究社区。我们的测绘中心，由7名新的研究人员组成，他们在单一- 细胞基因组技术和人类疾病分析，将与IGVF密切合作，分享技术， 资源、数据和组织样本，朝着开发全面的单细胞图谱的共同目标迈进 人类的细胞类型、功能调控元件和基因表达。

PROJECT SUMMARY/ABSTRACT A comprehensive genome-wide map of DNA regulatory elements and gene expression in human cells is of critical importance for understanding how genomic variation impacts human health and disease. Since regulatory DNA elements are exceptionally cell type-, tissue-, and disease state-specific, a comprehensive catalog of these elements has been difficult to achieve. The overall mission of this IGVF Mapping Center is to create a high- quality, open-access, and single cell-resolution reference map of human regulatory elements and gene expression in immune cells during human development, across organ systems in healthy adults, and in tissues from diverse immune-related diseases. Our Mapping Center will leverage: (i) our recent advances in developing scalable and cost-efficient single-cell epigenome and multi-omic technologies to simultaneously map open chromatin sites, gene expression, intracellular and cell surface proteins, and clonal lineage tracing in each tissue sample, (ii) our prior technical improvements and application of these methods to primary tissues from humans, and (iii) our pre-existing human tissue biobank consisting of samples from more than 500 human individuals, 20 organ systems, and 15 disease conditions, consented for unrestricted access, genomic sequencing, and data sharing. In Specific Aim 1, we will work closely with the IGVF Consortium to establish cross-center plans for data generation, analyses, and effective coordination of sample access and sharing. In Specific Aim 2, we will generate a single-cell multi-omic atlas of immune cell types (and non-immune cells types, as determined with the IGVF) during development in early life, healthy aging, and across human organ systems. In Specific Aim 3, we will generate a single-cell multi-omic atlas in immune cell types from primary tissues in patients with autoimmunity, cancer, neurodegenerative disease, and infection. In Specific Aim 4, we will analyze regulatory sites and gene expression in the context of clonal differentiation trajectories inferred from mitochondrial lineage tracing and develop and maintain an integrated reference map of each datatype and tissue sample for the research community. Our Mapping Center, composed of 7 new investigators with extensive experience in single- cell genomic technologies and human disease analysis, will work closely with the IGVF to share technologies, resources, data, and tissue samples towards the shared goal of developing a comprehensive single-cell atlas of cell types, functional regulatory elements, and gene expression in humans.