# Cardiomyocyte bromodomain protein 4 (BRD4) in physiology and disease

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $621,302

## Abstract

Project Summary
Together with the effects of modifier genes, sequence variants, endogenous factors, and
environmental cues, strong evidence points to epigenetic events contributing to heart failure
pathogenesis. Furthermore, epigenetic therapies have emerged already in oncology. Work from
our lab and others has demonstrated robust cardioprotective effects of small molecule inhibitors
of class 1 histone deacetylases (acetyl “erasers”) in both pressure-overload stress and
ischemia/reperfusion injury. In this proposal, we will turn our focus to the so-called “readers“ of
acetylation, the BRD proteins, specifically BRD4.
Prior work in the literature has demonstrated that a small molecule inhibitor of BRD proteins
blunts pathological cardiac remodeling, raising the tantalizing prospect of targeting this biology
for therapeutic gain. Depletion of specific BRD isoforms in those studies implicated BRD4.
Importantly, BRD4 encodes at least two isoforms in the heart (BRD-L and BRD-S) via
alternative exon usage. The long isoform BRD4-L is unique in the BET family in that it contains
an extended C terminus that includes a P-TEFb-interacting domain. BRD4 is known to regulate
superenhancers, large clusters of transcriptional enhancers that drive expression of genes that
define cell identity. Indeed, BRD4-L is required for super-enhancer function, with the C-terminal
domain necessary for the phase-shift occurring with formation of super-enhancer clusters. The
short isoform BRD4-S lacks this C terminus.
Beyond these structural differences, it is clear in the context of oncology and other domains
that these BRD4 isoforms have distinct – indeed antagonistic – functions, a fact which
complicates the interpretation of existing data in the cardiovascular space. Presently, nothing is
known about the role of these BRD4 isoforms in the heart.
Our preliminary data, using a cardiomyocyte-specific BRD4 knockout mouse, show that loss
of BRD4 results in a rapid decline in ventricular contractile function and dilated cardiomyopathy.
Our preliminary in vitro studies and in vivo studies targeting specific BRD4 isoforms suggests
that BRD4-L is not required for cardiac hypertrophy, but rather, the hypertrophic response is
dependent on BRD4-S. Here, we propose work based on the over-riding hypothesis that
specific isoforms of BRD4 play distinct roles in cardiomyocyte physiology and
pathology. Work to unveil isoform-specific functions will be a major step toward precision
targeting of this biology in disease therapy. Already, we have developed unique tools to directly
assess the roles of these isoforms both in vitro and in vivo.

## Key facts

- **NIH application ID:** 10049341
- **Project number:** 1R01HL147933-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** JOSEPH A HILL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $621,302
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049341

## Citation

> US National Institutes of Health, RePORTER application 10049341, Cardiomyocyte bromodomain protein 4 (BRD4) in physiology and disease (1R01HL147933-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10049341. Licensed CC0.

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