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Massively parallel characterization of variants and elements impacting transcriptional regulation in dynamic cellular systems

影响动态细胞系统转录调控的变异体和元件的大规模并行表征

基本信息

批准号：
10471968
负责人：
Nadav Ahituv
金额：
$ 179.83万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10471968
关键词：
Affect Biological Assay Biological Models Cardiac Cardiac Myocytes Catalogs Cells Characteristics Chromatin Computer software Coupling Data Data Set Development Disease Distal Elements Embryo Enhancers Gene Expression Gene Expression Regulation Genes Genetic Genomics Goals Heritability Human Human Biology Human Development Human Genetics Human Genome Individual Leadership Libraries Link Measurement Mediating Methods Modeling Mus Mutagenesis Mutate Mutation Neurologic Organoids Penetrance Phenotype Population Protocols documentation Rare Diseases Regulatory Element Reporter Rest Risk Role Severities System Technology Teratoma Testing Therapeutic Transcriptional Regulation Untranslated RNA Validation Variant Work cell type combinatorial data sharing directed differentiation disorder risk experience experimental study falls genetic variant genome editing genome-wide genomic variation human disease in vitro Model in vivo indexing nerve stem cell open source predictive modeling prime editing rare variant

项目摘要

SUMMARY / ABSTRACT A major fraction of heritability for common diseases, as well as for the penetrance and expressivity of rare diseases, partitions to distal regulatory elements in the human genome, overwhelmingly cell type-specific enhancers. However, a rate-limiting challenge for the field has been how to identify the specific variants, elements and regulated genes that mediate these effects on disease liability. Towards the overall goals of the Impact of Genomic Variation on Function (IGVF) Consortium, we propose to test over one million human regulatory elements or variants for their functional effects on transcriptional regulation, as well as to query over 100,000 distal regulatory elements for the gene(s) that they regulate. A first theme of our proposal is the diversity of multiplex technologies that we will employ to these ends, including massively parallel reporter assays (MPRAs), crisprQTL, saturation genome editing, multiplex prime editing and single cell combinatorial indexing, many of which we pioneered. A second theme is a focus on dynamic cellular systems that enable a given library of variants and/or elements to be tested across a broad range of cell types and states within a single experiment; these will include ESC-derived neuronal progenitors, cardiomyocytes, embryoid bodies, gastruloids and organoids, and in select cases, mice. A third theme involves leveraging our experience (e.g. CADD, a widely used, genome-wide catalog of variant effect predictions) to support the overarching goals of IGVF. Specifically, we envision using functional measurements generated by us and others to produce well-calibrated predictions of enhancer activity and variant effects that are continuous along the branching trajectories that comprise human development. Our specific aims are as follows: (1) To perform massively parallel validation and functional characterization of candidate human enhancers in a broad range of cell type contexts. (2) To perform massively parallel characterization of human genetic variants with potential roles in human disease. (3) To contribute to a comprehensive variant-element-phenotype catalog while taking a leadership role in synergistic interactions within IGVF, in the dissemination of methods, data and predictions, and in the overarching goals of the consortium.

摘要/摘要