# Investigating the role of H2A.Z dynamics in regulating cardiac lineage commitment

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $380,935

## Abstract

SUMMARY
Over the past 25 years, genetic studies in model systems, such as mouse, have revealed highly conserved
transcription factors (TFs) controlling human embryonic heart development. Although these studies have
identified causal mutations that contribute to congenital heart defects (CHD), we still do not know the molecular
causes associated with >80% of cases. Chromatin modulation acts to coordinate developmental signals and
TF activity, and disruption of chromatin structure is emerging as a major contributor to CHD, yet its roles are
least understood. This gap in our knowledge hinders our understanding of heart development and CHD,
slowing the development of breakthrough drugs to treat these devastating malformations. Our proposal
integrates innovative experimental and computational approaches to test the hypothesis that H2A.Z
incorporation by specific ATP-dependent remodeling complexes regulates critical cardiac gene ciruits
during lineage commitment. Notably, H2A.Z as well as components of its cognate remodeling complexes
have been linked to heart development and disease, however, their roles are poorly understood. Our extensive
preliminary work demonstrates that H2A.Z is enriched at promoter nucleosomes and acts as a molecular
rheostat to control transcriptional output by coordinating with histone “readers” and “writers”, supporting our
goal to dissect how these pathways functionally coordinate to regulate cardiac lineage commitment. Thus, we
expect that the impact of this proposal is several fold: 1) Dissecting how H2A.Z dynamics regulates cardiac
gene circuits represents a novel pathway for understanding how chromatin coordinates cardiac gene
regulatory networks. 2) Our approach will contribute new tools and insights into the pathways that are
disrupted in congenital heart defects (CHD). 3) Transcriptional control of embryonic heart development shares
many features with induction of pathological gene expression in response to injury or disease, thus, our study
opens the door for identifying potential new therapeutic targets for both CHD as well as pathological cardiac
hypertrophy. 4) Our proposed aims will generate large-scale, genomic data in mouse cardiac cell types that
can be immediately leveraged by the scientific community to enable additional discoveries. Finally, 5) the
recent association of genetic variants within conserved genes coding for Chromatin Remodelers in patients
with congenital and acquired heart defects indicates that our work will most certainly impact human health.

## Key facts

- **NIH application ID:** 10105353
- **Project number:** 5R01HL140471-04
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Laurie A Boyer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,935
- **Award type:** 5
- **Project period:** 2018-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105353

## Citation

> US National Institutes of Health, RePORTER application 10105353, Investigating the role of H2A.Z dynamics in regulating cardiac lineage commitment (5R01HL140471-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10105353. Licensed CC0.

---

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