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

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2022 · $29,481

## Abstract

1. A brief project 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 expres...

## Key facts

- **NIH application ID:** 10610129
- **Project number:** 3R01HL158081-01A1S1
- **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:** $29,481
- **Award type:** 3
- **Project period:** 2022-08-11 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10610129

## Citation

> US National Institutes of Health, RePORTER application 10610129, Role of BRD4 in Normal Hematopoiesis and Hematopoietic Stem Cell Biology. (3R01HL158081-01A1S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10610129. Licensed CC0.

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