High-throughput computational modeling to assess the role of 3D genome folding in human congenital heart defects

Active Project Grant Awarded Last action

Award ID
F31HL184670
Recipient
Awarding agency
Obligated
$43,101

Award facts

Assistance listing
93.837 Cardiovascular Diseases Research
Completion date 0% complete
Place of performance
San Francisco, CA 94143, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Congenital heart defects (CHDS) occur in nearly one percent of live births per year and are the leading cause of defect-associated infant mortality. Genetic studies in CHDS have focused on variation within the protein- coding exome. However, most disease-risk loci identified by genome-wide association studies (GWAS) fall in non-coding regions. IT is presumed that some of these represent regulators of gene expression such as CIS- acting enhancers and insulators. Despite these studies, less than half of the heritability of CHD has been explained via genome-wide associations or burden testing of protein-coding genes and putative regulatory elements. In this proposal, I hypothesize that genetic variants that alter 3D genome folding contribute to the etiology of CHD by disrupting the contacts of CIS-regulatory elements near key developmental genes. A key chromatin structure potentially affected is the topologically associating domain (TAD). Tads have been characterized as a chromatin structure promoting higher contact frequency within the domain relative to loci outside of that domain. IT has been shown that regions making higher contact frequency include contacts between enhancers and promoters necessary for gene expression. Formation of tads is mediated by ctcf, a DNA-protein binding factor that recognizes a specific DNA binding sequence. While unaffected controls show a clear depletion of structural variants (SVS) at TAD boundary regions across the genome, individuals diagnosed with developmental delay (DD) showed no bias in the genomic location of SVS. From these findings and the high rates of CO-morbidity between DD and CHD, aim 1 will create a deep learning model that learns the relationship between DNA sequence and chromatin contact points specific to cardiac cells. By learning which DNA sequences contribute to chromatin folding, this model will decipher and distinguish which sequence elements harbored in CHD SVS potentially contribute to the disruption of chromatin folding. This will further determine whether SVS are enriched for ctcf binding sites critical for TAD formation. In aim 2, I will computationally predict and evaluate chromatin contact changes from hundreds of genetic SVS in CHD patients compared to SVS found in controls. I will score and identify CHD SVS that are highly disruptive to chromatin folding and elucidate potential mechanisms, such as disruption of ctcf binding sites. In collaboration with an experimental lab, I will confirm model-predicted chromatin contact effects for 3D genome chromatin interactions and gene expression in cell lines edited to carry the patient's genetic variant versus an isogenic cell line without the variant. My role will be to analyze the genomic data and quantify differences between the predictions and the experiments. Results of this proposal will elucidate the role of the 3D genome organization in CHD, provide interpretation for non-coding variants associated with CHD, and demonstrate the potential of deep learning models for high-throughput prediction of chromatin contact frequency.

Quick answers

Who received award F31HL184670?

F31HL184670 was awarded to The Regents Of The University Of California. San Francisco by National Heart Lung and Blood Institute (National Institutes of Health) on December 1, 2026.

How much is award F31HL184670 worth?

$43,101 has been obligated on F31HL184670.

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