# Regulation of Cardiomyocyte Maturation

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $588,788

## Abstract

Project Summary/Abstract
 Adult cardiomyocytes (CMs) are specialized to forcefully contract and relax billions of times during an
animal's lifetime. A number of adaptations allow adult CMs to fulfill this role, including: large, elongated shape;
highly organized network of cell-cell junctions; reliance on oxidative metabolism; nearly crystalline array of
sarcomeres; characteristic organization of calcium release units around a network of plasma membrane
invaginations known as T-tubules; cell cycle exit; and expression of adult CM-specific contractile, calcium
handling, and ion channel genes. In mouse, most of these adaptations are acquired in the first three postnatal
weeks. Little is known about the molecular regulation of the CM maturation program. This information gap
limits development of rational approaches to stimulate maturation of stem-cell derived CMs. Furthermore, it is
likely that congenital heart disease mutations or abnormal cardiac stress caused by congenital heart
malformations impact CM maturation, with implications for long term myocardial performance of congenital
heart disease patients.
 Our long term goal is to understand the regulatory program that governs CM maturation. Our
preliminary data show that GATA4 and GATA6 (GATA4/6) transcription factors are essential for CM
maturation. In addition, a forward genetic screen uncovered TAF3, a component of the RNA Polymerase II
pre-initiation complex and a reader of H3K4me3 epigenetic marks, as a novel maturation regulators. Using a
number of unique and novel tools and approaches, this proposal will investigate mechanisms that control CM
maturation. Aim 1 will dissect the mechanisms by which GATA4 and GATA6 regulate enhancer activity during
CM maturation. Aim 2 will further characterize TAF3 mutants and dissect the mechanisms by which it regulates
maturation. Aim 3 will apply our innovative in vivo forward genetic screen to discover signaling molecules and
congenital heart disease genes that are essential for CM maturation.
 The coordinated transformation of fetal CMs to their mature counterparts is among the least well
understood aspects of cardiac development. Success with this proposal's aims will advance our knowledge in
this unexplored frontier of cardiac development.

## Key facts

- **NIH application ID:** 10114150
- **Project number:** 5R01HL146634-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** William Tswenching Pu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $588,788
- **Award type:** 5
- **Project period:** 2019-03-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114150

## Citation

> US National Institutes of Health, RePORTER application 10114150, Regulation of Cardiomyocyte Maturation (5R01HL146634-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10114150. Licensed CC0.

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