A Foundational Resource of Functional Elements, TF footprints and Gene Regulatory Interactions

功能元件、转录因子足迹和基因调控相互作用的基础资源

• 批准号: 10640985
• 负责人: BRADLEY Evan BERNSTEIN
• 金额: $ 239.57万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-09 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640985
• 关键词: Affect; Antibodies; Autoimmune Diseases; Bar Codes; Binding; Binding Sites; Biological Assay; Biology; Blood; Brain; Cadaver; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Cell model; Cells; Cellular Assay; Chromatin; Classification; Code; Collaborations; Collection; Communities; Consent; Consultations; DNA; Data; Data Set; Development; Disease; Elements; Endocrine; Enhancers; Event; Experimental Models; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic; Genetic Variation; Genomic medicine; Genomics; Genotype; Goals; Harvest; Human; Human Genetics; Human Genome; Immune; Maps; Metabolic; Metabolic Diseases; Microglia; Modeling; Modification; Mutation; Neurodegenerative Disorders; Neurons; Operative Surgical Procedures; Organoids; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Process; Production; Proteins; Quantitative Trait Loci; RNA; Recovery of Function; Regulator Genes; Regulatory Element; Research; Research Personnel; Resolution; Resources; Risk; Sampling; Specificity; Specimen; Standardization; Technology; Tissue Model; Tissues; Transcript; Transposase; Untranslated RNA; Variant; Work; cell type; cohort; computerized tools; cost effective; data integration; design; ethnic diversity; experience; gastrointestinal; gene interaction; genetic variant; genome-wide; genomic variation; histone modification; human disease; human genomics; human model; human tissue; induced pluripotent stem cell; innovation; multiple omics; nerve stem cell; neuropsychiatric disorder; personalized medicine; promoter; response; single-cell RNA sequencing; trait; transcription factor

PROJECT SUMMARY This project aims to assemble a foundational resource of functional DNA elements, transcription factor (TF) binding sites and gene regulatory interactions for the Impact of Genomic Variation on Function (IGVF) consortium. The resource will facilitate interpretation of noncoding genetic variation associated with human traits and diseases, advance understanding of disease mechanisms and hasten progress towards genomic medicine. A large majority of genetic variants associated with human diseases are non-coding, which has hindered their interpretation and utility for understanding disease. Non-coding disease variants are enriched within promoters, enhancers and TF binding sites. Hence, a compelling hypothesis is that they modulate the activity of functional elements, TF interactions and gene targets in specific cellular contexts. To interpret the function of a variant, investigators must determine the element and/or TF that they impact, which gene is affected, and the cell state in which the effect is manifested. This process is greatly facilitated by genome-wide maps of functional elements, TFs and regulatory interactions. However, existing resources under-represent disease-relevant functional elements that are specific to early developmental stages, rare cell states, physiological responses, genotypes or disease states. To overcome these limitations, the proposed project will deploy an innovative suite of single-cell assays to profile RNA transcripts, chromatin accessibility, TF footprints and histone modifications at unprecedented scale. These assays will be applied to an expansive collection of phenotypically- and genotypically-diverse BioSamples selected for their relevance to cardiovascular, metabolic, autoimmune, neuropsychiatric and neurodegenerative diseases. We will acquire >16 million single-cell profiles for thousands of BioSamples that span cadaveric tissues, surgical specimens, peripheral blood mononuclear cell (PBMC) cohorts, brain organoids and other innovative experimental models. Integration of this vast dataset will enable us to (1) annotate millions of regulatory elements and TF motifs; (2) predict gene targets from co-variation of element accessibility and gene expression across single cells; and (3) identify quantitative trait loci for gene expression (eQTLs) and chromatin accessibility (caQTLs) from the diverse genotypes represented in our cohorts. The project will bring together a diverse team of experts in human genetics, disease biology, genomics and production research. The team will coordinate closely with IGVF colleagues and the DACC in the design, assembly and integration of this resource. All data will be made freely available and maximally accessible to the scientific community, with the goal to catalyze human genetics, disease biology and genomic medicine.

项目摘要 该项目旨在组装功能性DNA元件的基础资源，转录因子（TF） 基因组变异对功能影响的结合位点和基因调控相互作用（IGVF） 财团该资源将有助于解释与人类相关的非编码遗传变异。 性状和疾病，推进对疾病机制的理解，并加快基因组 药 绝大多数与人类疾病相关的遗传变异是非编码的， 阻碍了它们的解释和理解疾病的效用。非编码疾病变异体富集 在启动子、增强子和TF结合位点内。因此，一个令人信服的假设是，他们调节 功能元件的活性，TF相互作用和特定细胞环境中的基因靶点。解释 为了确定变异的功能，研究人员必须确定它们影响的元件和/或TF， 受影响的，和细胞的状态，其中的效果是体现。这一过程在很大程度上是由全基因组 功能元件、转录因子和调控相互作用的图谱。然而，现有资源未充分体现 疾病相关的功能元件，其特异于早期发育阶段，稀有细胞状态， 生理反应、基因型或疾病状态。 为了克服这些局限性，拟议的项目将部署一套创新的单细胞测定 以前所未有的速度分析RNA转录本、染色质可及性、TF足迹和组蛋白修饰， 规模这些检测将应用于表型和基因型多样性的广泛收集。 生物样品的选择是因为它们与心血管、代谢、自身免疫、神经精神和 神经退行性疾病我们将为数千个生物样品获取超过1600万个单细胞图谱， 跨越尸体组织、手术标本、外周血单核细胞（PBMC）队列、脑 类器官和其他创新的实验模型。整合这个庞大的数据集将使我们能够（1） 注释数以百万计的调控元件和TF基序;（2）从元件的共变异预测基因靶点 跨单细胞的可接近性和基因表达;以及（3）鉴定基因表达的数量性状位点 在此基础上，我们对来自我们的队列中所代表的不同基因型的eQTL和染色质可及性（caQTL）进行了比较。 该项目将汇集人类遗传学、疾病生物学、基因组学和 生产研究。该团队将在设计中与IGVF同事和DACC密切协调， 整合和整合这些资源。所有数据都将免费提供，并尽可能让以下人员访问 科学界，目标是促进人类遗传学，疾病生物学和基因组医学。