UM1HG011986

A Foundational Resource of Functional Elements, TF Footprints, and Gene Regulatory Interactions - 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 the 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 an 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 over 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.

The Broad Institute

NHGRI SUPPORTS THE DEVELOPMENT OF RESOURCES AND TECHNOLOGIES THAT WILL ACCELERATE GENOME RESEARCH AND ITS APPLICATION TO HUMAN HEALTH AND GENOMIC MEDICINE. A CRITICAL PART OF THE NHGRI MISSION CONTINUES TO BE THE STUDY OF THE ETHICAL, LEGAL AND SOCIAL IMPLICATIONS (ELSI) OF GENOME RESEARCH. NHGRI ALSO SUPPORTS THE TRAINING AND CAREER DEVELOPMENT OF INVESTIGATORS AND THE DISSEMINATION OF GENOME INFORMATION TO THE PUBLIC AND TO HEALTH PROFESSIONALS. THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM IS USED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM IS USED TO FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.172 - Human Genome Research

National Human Genome Research Institute (NHGRI) [HHS - NIH]

Cambridge, Massachusetts 021421027 United States

Single Zip Code

Single-cell Profiling of Regulatory Element and Gene Activity in Relationship to Genome Function (UM1 Clinical Trial Not Allowed) (RFA-HG-20-045)

Amendment Since initial award the total obligations have increased 731% from $1,332,140 to $11,067,103.