# Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $310,000

## Abstract

Bromodomain-containing protein 4 (BRD4) is a member of the BET (bromodomain and extra terminal domain)
family proteins that also include BRD2, BRD3, and BRDT. BRD4 facilitates the initiation and elongation of
transcription by binding to acetylated lysine residues of histone tails to promote the recruitment of the RNA
polymerase II complex to sites of active transcription. Since BRD4 is required for MYC oncogene expression,
BRD4 inhibition represents an attractive strategy to target MYC-dependent cancers via small-molecule inhibitors.
BRD4 is over-expression in both solid tumors and myeloid malignancies, including acute myeloid leukemia (AML).
BET inhibitors (BETi) have been shown to have efficacy against various types of tumors, especially MYC-driven
cancers. Despite robust studies of BRD4 in solid tumors, the role of BRD4 in normal hematopoiesis and the
impact of BRD4 overexpression on the pathogenesis of hematological malignancies remain largely unknown.
Filling this critical gap of knowledge is the primary goal of this 3-year SHINE application. In the current project,
we aim to determine the roles of BRD4 in hematopoietic stem/progenitor cells (HSC/HPCs) function and
explore whether Brd4 overexpression affects HSC/HPC cell fate and leukemic transformation. Using a
conditional Brd4 knock- out (Mx1Cre;Brd4f/f) mouse model, we found that while heterozygous deletion of Brd4
in mice did not cause noticeable changes in hematopoiesis, homozygous deletion of Brd4 in the hematopoietic
system quickly diminished HSC/HPCs and pan lineage cells due to the induction of apoptosis. Therefore, the
conditional Brd4 knock-out mouse model alone is not suitable for studying the hidden role of BRD4 in
HSC/HPC functions. We thus generated several Brd4 transgenic (Tg) mouse lines with different levels of BRD4
transgene expression (ranging from 25% to 200%). Our preliminary data showed that overexpression of BRD4
(Brd4200%Tg) in hematopoietic cells altered HSC/HPC pools in vivo and increased HSC/HPC replating potential
in vitro. Interestingly, re-expression of a lower level of BRD4 in Brd4Δ/Δ BMMNCs (Brd4Δ/Δ;Brd425%Tg)
significantly increased the cell survival and the frequencies of CFU-Cs. We hypothesize that a hypomorph
BRD4 mouse model (Mx1Cre;Brd4f/f;Brd425%Tg), by expressing a protectable level of BRD4 in hematopoiesis
which allow for HSC/HPC survival, would suit better for evaluating the hidden role of BRD4 in HSC/HPC
functions. We will also examine whether BETi affect normal hematopoiesis in mice. Furthermore, we will
decipher how BRD4 regulates the HSC/HPCs functions by assessing genome-wide BRD4, P-TEFb, Pol-II,
H3K27ac, and H3K122ac occupancies in HSC/HPCs and correlating with the gene expression outputs. These
studies are timely and fundamentally crucial for filling an essential and critical gap of knowledge towards
uncovering the hidden roles of BRD4 in normal and malignant hematopoiesis, thus fill a critical gap in
knowledge on Brd4 in hematopoiesis and B...

## Key facts

- **NIH application ID:** 10744741
- **Project number:** 5R01HL158081-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Feng-Chun Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $310,000
- **Award type:** 5
- **Project period:** 2021-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744741

## Citation

> US National Institutes of Health, RePORTER application 10744741, Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology (5R01HL158081-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10744741. Licensed CC0.

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