# Transcriptional regulation of cardiac morphogenesis

> **NIH NIH P01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $479,188

## Abstract

ABSTRACT
 Congenital heart disease (CHD) is the most common birth defect. Among various CHDs, single ventricle
phenotypes resulting from altered ventricular morphogenesis have the poorest clinical prognoses. CHDs that
present with defective ventricular morphogenesis allow for the mixing of oxygenated and deoxygenated blood
via ventricular septal defects (VSDs) and/or impaired contractile function both of which put limits on vitality.
Currently, there is a poor understanding of the molecular mechanisms and cellular etiology causative of the many
forms of ventricular CHDs.
 Hand1 is expressed within the developing left ventricle (LV) myocardium and the myocardial cuff (MC)
between embryonic day (E) E8.5 and E13.5. HAND1 is established as required for normal LV and cardiac
conduction system morphogenesis. Cardiomyocyte deletion of Hand1 results in surviving mice that present with
CHDs effecting LV morphology and cardiac function. HAND1 single nucleotide polymorphisms have been
identified in patients diagnosed with QRS conduction defects. These HAND1 polymorphisms reside within an
evolutionarily conserved transcriptional enhancer, and act by disrupting GATA factor DNA binding. Hand1 gene
expression is downregulated by the loss-of function of chromatin organizing protein CTCF within cardiomyocytes.
Our preliminary data show that HAND1 is organized into a single topologically active domain (TAD) that isolates
Hand1 from other genes within the TAD loop concurrent with its expression. Further examination of the epigenic
regulation of the HAND1 locus is needed to elucidate how chromatin organization modulates the expression of
critical morphogenetic transcription networks within LV cardiomyocytes. In other studies, we will determine
HAND1 DNA occupancy within the genome, evaluate the changes in cardiomyocyte expression within occupied
genes, and identify key transcriptional partners that interact with HAND1 to facilitate its role in ventricular
morphogenesis.
RELEVANCE
 CHDs resulting in ventricle phenotypes have the poorest clinical outcomes. Thus, gaining a better
understanding of the etiology and molecular mechanisms that cause CHDs resulting in altered ventricular
morphogenesis has the potential to benefit thousands of pediatric patients annually. As HAND1 plays a key role
in cardiomyocyte patterning, gaining insight into the cellular and molecular mechanism of this understudied
developmental process is critical for informing the development of non-surgical treatments for CHD patients.

## Key facts

- **NIH application ID:** 10755286
- **Project number:** 5P01HL134599-07
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Anthony B. Firulli
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $479,188
- **Award type:** 5
- **Project period:** 2017-02-15 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755286

## Citation

> US National Institutes of Health, RePORTER application 10755286, Transcriptional regulation of cardiac morphogenesis (5P01HL134599-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10755286. Licensed CC0.

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