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

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $24,611

## Abstract

A brief summary of the parent grant. The parent grant of this supplemental fund application is
1R01HL158081-01A1, entitled “Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem
Cell Biology”, which was approved for funding from 12/01/2021 to 11/30/2024.
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 Brd4Ä/Ä BMMNCs
(Brd4Ä/Ä;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 outpu...

## Key facts

- **NIH application ID:** 10610534
- **Project number:** 3R01HL158081-01A1S2
- **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:** 2022
- **Award amount:** $24,611
- **Award type:** 3
- **Project period:** 2022-08-11 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10610534

## Citation

> US National Institutes of Health, RePORTER application 10610534, Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology_ (3R01HL158081-01A1S2). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10610534. Licensed CC0.

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