# Mapping Functional Variation in Gene Regulatory Dynamics during Human Cardiomyocyte Differentiation

> **NIH NIH F31** · UNIVERSITY OF CHICAGO · 2020 · $45,389

## Abstract

PROJECT SUMMARY:
 Cardiovascular disease (CVD) refers to a range of complex disorders that together represent the
leading cause of death worldwide. Genetic loci contributing to disease risk have been identified in genome
wide association studies. Many of these loci lie in noncoding regions of the genome and have unknown
function, but are thought to influence disease risk through regulatory activity. Such regulatory variants may only
act in a particular cell type or at a particular time. There is strong evidence that regulatory variants acting
during development can impact heart health both in the short term and in the long term, contributing to both
congenital heart diseases and later-onset CVDs. However, developmental processes in human cells have
been historically understudied due to ethical limitations regarding the use of human fetal tissue. Today, these
ethical limitations can be overcome using human induced pluripotent stem cells (iPSCs) as a model. iPSCs
can be differentiated into a variety of cell types including cardiomyocytes, the muscle cells that make up most
of the heart by mass. Protocols for differentiation of iPSC derived cardiomyocytes are well established, highly
efficient, and the resulting cells are a faithful model of primary human heart tissue.
 I propose to study gene regulation in a timecourse of cardiomyocyte differentiation using human iPSCs
as a model. In my Aim 1, I will apply genome-wide techniques to assay two regulatory phenotypes - gene
expression and chromatin accessibility - every 24 hours during the 16 day differentiation in a sample of 70
individuals; this will provide a high-resolution profile of inter-individual variation in temporal dynamics of gene
regulation in differentiating cardiomyocytes. Then, in Aim 2, I will identify genetic variants that are associated
with the developmental dynamics of gene regulation using a quantitative trait loci (QTL) analysis framework. I
will first identify standard, static QTLs within each time point of the differentiation. Next, I will analyze data from
all time points together to identify dynamic QTLs, QTLs that are associated with differences in gene regulation
at some but not all time points. Finally, in Aim 3, I will combine the QTLs I discovered in my data with published
GWAS for CVD risk to understand the ways in which regulatory variants controlling developmental dynamics
contribute to cardiovascular diseases. Overall, this study leverages powerful genomic technologies and
recently developed iPSC techniques to uncover the mechanisms through which regulatory variants acting
during development impact disease risk, ultimately deepening our understanding of the molecular
underpinnings of CVD.

## Key facts

- **NIH application ID:** 9960311
- **Project number:** 5F31HL146171-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Katherine Louise Rhodes
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,389
- **Award type:** 5
- **Project period:** 2019-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960311

## Citation

> US National Institutes of Health, RePORTER application 9960311, Mapping Functional Variation in Gene Regulatory Dynamics during Human Cardiomyocyte Differentiation (5F31HL146171-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9960311. Licensed CC0.

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