U01HG012047

Defining Causal Roles of Genomic Variants on Gene Regulatory Networks with Spatiotemporally-Resolved Single-Cell Multiomics - Project Summary

A fundamental question in biology is to understand how genetic variation affects genome function to influence phenotypes. The majority of genetic variants associated with human diseases are located within non-coding genomic regions and may affect genome functions and phenotypes through modulating the activity of cis-regulatory elements and cell-type specific gene regulatory networks (GRNs). However, our knowledge about the impact of genomic variants (alone or as combinations) on gene expression, GRN activity, and ultimately cellular phenotypes are rather limited.

Furthermore, because transcription factors (TFs) and related cis-regulatory elements are known to have distinct functions based on cell-type and state, how genomic variants influence cell-type/state-specific activity of functional elements and phenotypes remains to be characterized in much greater detail.

This proposal aims to leverage a panel of multi-ethnic, gender-balanced human induced pluripotent stem cell (hiPSC) lines (European, African American, and African hunter-gatherers), as well as recent advances in single-cell time-resolved or multi-omics technologies, predictive modeling of regulatory networks by machine learning, and high-throughput single-cell perturbation methods to study the functional impact of genomic variations on regulatory networks and cellular phenotypes.

First, we will establish a robust experimental framework of deploying advanced time-resolved and multi-omic single-cell technologies for detecting functional genetic variants at the single-cell level. Next, we will develop novel computational methods for integration of single-cell data across different modalities and for accurate reconstruction and predictive modeling of GRNs driving cellular identity and developmental dynamics (cardiac and neural lineage cell fate transition).

Finally, we will apply high-throughput combinatorial genetic or epigenetic perturbation approaches to modulate the activity of key genes or putative cis-regulatory elements at single-cell levels to improve our understanding of network-level relationships among genomic variants and phenotypes.

Trustees Of The University Of Pennsylvania

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]

Philadelphia, Pennsylvania 19104 United States

Single Zip Code

Defining Genomic Influence on Gene Network Regulation (U01 Clinical Trial Not Allowed) (RFA-HG-20-044)

Amendment Since initial award the total obligations have increased 396% from $1,210,000 to $6,001,599.