# Transcriptional regulation of cardiac morphogenesis

> **NIH NIH P01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $499,141

## 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. Gene targeting models establish that Hand1 is required for
normal LV development. We show that cardiomyocyte deletion of Hand1 results in surviving mice that present
with CHDs effecting LV morphology. Recently, HAND1 mutations have been identified in patients diagnosed
with CHDs. These HAND1 gene mutations manifest as frameshift or nonsense mutations within the protein
coding domains and are reported to be somatic in nature, as germline mutations in HAND1 are assumed to be
embryonic lethal. Like all genes, Hand1 is transcriptionally regulated through cis-element enhancers located
within Conserved Non-coding Sequences (CNS) that are present both 5' and 3' to the Hand1 transcriptional
start site. The notion that CNS gene mutations affecting the function of Hand1 through defects in cardiac
transcriptional regulatory elements is a largely unexplored hypothesis that could provide a mechanism for
heritable Hand1 cardiac loss-of-function in human CHDs.
RELEVANCE
CHDs resulting in ventricle phenotypes have the poorest clinical outcomes. Thus, gaining an 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. Hand1 plays a key role in cardiomyocyte
patterning and gaining insight into the cellular and molecular mechanism of this understudied developmental
process will have a great benefit to developing non-surgical treatments for CHD patients.

## Key facts

- **NIH application ID:** 9855063
- **Project number:** 5P01HL134599-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Anthony B. Firulli
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $499,141
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855063

## Citation

> US National Institutes of Health, RePORTER application 9855063, Transcriptional regulation of cardiac morphogenesis (5P01HL134599-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9855063. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*