# Project 2: Regulation of cardiac gene regulation and differentiation by dynamic chromatin remodeling complexes

> **NIH NIH P01** · J. DAVID GLADSTONE INSTITUTES · 2021 · $585,934

## Abstract

PROJECT SUMMARY/ABSTRACT
PROJECT 2
Congenital heart defects (CHDs) are among the most common and devastating birth defects in humans,
occurring in about 1% of live births and resulting in significant mortality and morbidity. We have very little
understanding of the processes that, when gone awry, cause CHDs. Human genetics have uncovered
mutations in transcription factors (TFs) and chromatin remodeling factors as the underlying etiology of several
CHDs. Thus, understanding the function of these critical regulators of cell identity and function is crucial. The
function of TFs is intimately related to and regulated by the status of the chromatin at their target binding sites.
Chromatin structure affects the accessibility and activity of TFs. Therefore, the regulation of chromatin
structure is critical for controlling transcription. Chromatin remodeling occurs largely via ATP-dependent
chromatin remodeling complexes, which alter the structure of histone-associated DNA to allow access to the
transcriptional machinery. By immunoprecipitation of complexes followed by mass spectrometry (IP-MS) we
identified the stoichiometrically regulated components of dynamic BAF complexes during in vitro cardiac
differentiation. BAF60c and BAF170 are preferably included in cardiac BAF complexes, as are newly identified
subunits such as WDR5, which is mutated in human CHD. Genetic ablation of BRG1, BAF60c, or BAF170
revealed essential roles in activating and maintaining the cardiac program. We further examined BAF60c- and
BAF170-containing complexes, and identified an additional subset of complexes that include the alternate
ATPase, BRM. We find that BRM is strikingly essential for activation of the cardiogenic program: In the
absence of BRM, CP transcriptional regulators fail to be activated, leading to catastrophic failure of
cardiogenesis, with cells instead adopting alternate fates. We hypothesize that specific BAF complexes form
dynamically to coordinate regulation of distinct aspects of cardiac morphogenesis and lineage decisions. We
will test this hypothesis in three Specific Aims: 1. To uncover the molecular mechanisms by which dynamic
BAF complex subunits regulate specific gene expression programs. 2. To determine the functional importance
of the BAF complex subunit switch in cardiomyocyte differentiation. 3. To decipher the redundant and specific
roles played by the interchangeable BAF complex subunits. The knowledge generated from this study,
integrating the data generated in the other PPG projects, will be crucial to our understanding of the
transcriptional regulation of cardiac development, and mechanisms underlying CHDs. Importantly, we will gain
significant insight into the basis of the integration of cardiac TFs with chromatin remodeling complexes, and the
broad set of essential interactions that lead to finely tuned regulation of cardiac gene expression.

## Key facts

- **NIH application ID:** 10245030
- **Project number:** 5P01HL146366-03
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** Benoit Gaetan Bruneau
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $585,934
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245030

## Citation

> US National Institutes of Health, RePORTER application 10245030, Project 2: Regulation of cardiac gene regulation and differentiation by dynamic chromatin remodeling complexes (5P01HL146366-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245030. Licensed CC0.

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