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 该项目旨在汇总功能性DNA元素的基础资源，转录因子（TF） 结合位点和基因调节相互作用对基因组变异对功能的影响（IGVF）的影响 财团。该资源将促进与人类相关的非编码遗传变异的解释 特征和疾病，提高对疾病机制的理解并加速基因组的进步 药品。 与人类疾病相关的绝大多数遗传变异是非编码的，它具有 阻碍了他们理解疾病的解释和效用。非编码疾病变体富集 在启动子，增强子和TF结合位点。因此，一个令人信服的假设是它们调节 在特定细胞环境中功能元件，TF相互作用和基因靶标的活性。解释 变体的功能，研究人员必须确定其影响的元素和/或TF，哪个基因是 受影响，以及表现出效果的细胞状态。整个基因组都大大促进了这个过程 功能元素，TFS和调节性相互作用的地图。但是，现有资源不足 特定于早期发育阶段，稀有细胞状态，与疾病相关的功能元素， 生理反应，基因型或疾病状态。 为了克服这些限制，拟议的项目将部署一套创新的单细胞测定法 在前所未有的 规模。这些测定将应用于广泛的表型和基因型多样性的集合 为了与心血管，代谢，自身免疫性，神经精神病学和 神经退行性疾病。我们将为成千上万的生物样本获得> 1600万个单细胞配置文件 SPAN尸体组织，手术标本，外周血单核细胞（PBMC）队列，大脑 器官和其他创新的实验模型。该广泛数据集的集成将使我们能够（1） 注释数百万的监管元素和TF图案； （2）预测基因靶标从元素的共变量 跨单细胞的可及性和基因表达； （3）确定基因表达的定量性状基因座 （EQTL）和染色质可及性（CAQTL）来自我们队列中代表的不同基因型。 该项目将汇集一个多样化的人类遗传学，疾病生物学，基因组学和 生产研究。团队将与IGVF同事和设计中的DACC紧密协调， 集合和集成此资源。所有数据将免费提供，并可以最大地访问 科学界的目标是催化人类遗传学，疾病生物学和基因组医学。