# Regulation of Chromatin Signaling in Heart Failure by the BRD4 Bromodomain Protein.

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $745,398

## Abstract

Abstract
Despite current standard of care, a diagnosis of heart failure (HF) is associated with poor quality-of-life and a
5-year mortality approaching 50%. In light of this urgent unmet need, the elucidation of novel mechanisms
involved in HF pathogenesis holds promise for identifying new therapies for this prevalent and deadly disease.
The PIs of this application were the first to illustrate a crucial role for a conserved family of acetyl-lysine
“reader” proteins (BET bromodomains) in the transcriptional control of HF. Importantly, these studies
leveraged the use of JQ1, a first-in-class, specific small molecule inhibitor of BET bromodomains. This multi-PI
renewal application seeks to vertically advance our understanding of how aberrant chromatin-dependent signal
transduction (via the BET family member BRD4) drives pathologic cardiac fibrosis. Our long-term objective is
to develop BRD4 inhibition as a novel therapeutic strategy in HF. Exciting preliminary studies demonstrate that
BRD4 mediates cardiac fibroblast activation in vitro, and that BRD4 inhibition with JQ1 suppresses cardiac
fibrosis in mouse models of HF. Mechanistically, we demonstrate that BRD4 functions downstream of pro-
fibrotic TGF- signaling by binding to regulatory enhancers that drive a gene program of myofibroblast
(myoFB) activation. This proposal will test the central hypothesis that BRD4 functions as a nodal
transcriptional regulator of pathological cardiac fibrosis that can be pharmacologically targeted in vivo. Guided
by strong preliminary data, this hypothesis will be tested by pursuing three robust specific aims: (1) Discover
the gene-specific role of BRD4 in cardiac myoFB in vivo; (2) Dissect the chromatin-dependent signaling
mechanisms governing BRD4-dependent activation of endogenous cardiac myoFBs; (3) Define the roles of
specific BRD4 functional domains in the control of cardiac myoFB activation. Several innovative tools that were
developed during the first funding period will be employed to advance this new avenue of investigation,
including floxed Brd4 mice, Brd4-3XFLAG knock-in mice, Brd4 bromodomain knock-in mice, as well as
peptides and small molecules that selectively inhibit distinct functional domains in BRD4. The proposed
research is significant because it will facilitate development of pharmacologic BRD4 inhibition as a novel
therapeutic strategy in HF, and therefore addresses an enormous unmet clinical need. Our proposal is highly
innovative because we successfully “drug” pro-fibrotic transcription and remodeling via unprecedented
approaches, we define the functions of BRD4 in cardiac fibroblasts for the first time, and we provide the first
epigenomic evaluation of cardiac fibroblasts. Given the synergistic expertise of our consortium, we envision
that sustained contributions from our highly-collaborative group will pave the way for the development of novel
“epigenetic therapies” for cardiovascular disease.

## Key facts

- **NIH application ID:** 10434776
- **Project number:** 5R01HL127240-08
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Timothy McKinsey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $745,398
- **Award type:** 5
- **Project period:** 2015-04-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434776

## Citation

> US National Institutes of Health, RePORTER application 10434776, Regulation of Chromatin Signaling in Heart Failure by the BRD4 Bromodomain Protein. (5R01HL127240-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10434776. Licensed CC0.

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