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BRD4: Epigenetic Regulator and Emerging Cancer Target


Bromodomain protein 4 (BRD4) is a transcriptional regulator that plays a key role in cancer, autoimmunity, and inflammatory diseases1,2. BRD4 was discovered as a protein bound to acetylated chromatin during cell cycle progression. In this way BRD4 maintains consistent gene expression during subsequent rounds of division, a phenomenon known as epigenetic memory or "bookmarking" for gene transcription2,7. BRD4 also plays a critical role in regulating differentiation and development2,4. In the absence of BRD4, bone marrow stem cells are unable to generate B and T cells2. BRD4 is required for the re-expression of stem cell genes during reprogramming of MEFs or B cells to induced pluripotent stem cells2, and also plays a role in osteoblast differentiation4. The role of BRD4 in cell cycle control and differentiation has made it an emerging therapeutic target for cancer and immune system pathologies.

Human BRD4

Diagram of full length human BRD4 showing its four primary functions: (1) binding to acetylated chromatin via two N terminal bromodomains (BD1, BD2); (2) histone acetyl transferase (HAT) activity for acetylating lysine residues in histones, (3) serine kinase activity which acts on RNA pol II; and (4) a C-terminal motif (CTM) which serves as a nucleation site for transcription factors. The extraterminal (ET) domain is characteristic of BET family members and serves as an additional protein-protein interaction domain.


The BET family of bromodomain proteins are characterized by the presence of two bromodomains and an ET domain2,6. Of these, BRD4 is the most well-studied. BRD4 has four primary molecular functions. It (i) maintains chromatin structure via binding acetylated histones, an activity mediated by sites in the N-terminal domain; (ii) Histone Acetyl Transferase (HAT) activity via its HAT catalytic domain2,6; (iii) serine kinase activity via a kinase domain that spans the N-terminal region and phosphorylates residues in the C-terminal domain of RNA Pol II2,6; and (iv) the C-terminal domain serves as a binding and nucleation site for transcription factors and complexes. BRD4 is found in several transcription complexes, including the general cofactor Mediator and the P-TEFb elongation factor6. The C terminal domain also mediates the interactions of BRD4 with many well-known transcriptional regulators, most notably P-TEFb, MYC, NFκb, and p532,4,6-8.

BRD4 has recently come to light as a possible target for cancer therapy because of its role as a transcriptional and epigenetic regulator of the cell cycle1-5. In particular, many hematopoietic cancers depend on constant BRD4 activity for expression of Myc2,3,5,7. Solid tumors are also associated with BRD4 activity2. Deregulation of BRD4 is clinically linked to breast, colon, and prostate cancers7. Interestingly, a BRD4 fusion protein, BRD4-NUT, is found in aggressive midline carcinomas2,7. Whether BRD4 plays a further role in metastasis is unclear2.

To date, most available BET inhibitors affect all BET family members producing unpredictable and sometimes dangerous results1. BET inhibitors work by blocking the association of BRD4 with chromatin by mimicking acetyl-lysine residues on histones2,3.This effect prevents transcription of Myc and other critical regulatory genes leading to cell cycle arrest2,3,5. Specific BET inhibitors are currently under development which will allow more selective inhibition of BRD4 and other BET family members1,3,5,7. BET inhibitors may be especially effective in combination with a variety of other chemotherapeutic agents by enabling the use of lower doses of toxic drugs and by helping to overcome resistance5,7.

Recognizing its importance in cell cycle regulation and tumorigenesis, Bethyl manufactures rigorously tested antibodies to BRD4 and many other related proteins to promote the advancement of cancer research.


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Studies show only 50% of antibodies can be trusted to work the way they’re designed to.* That’s where Bethyl is different. We have been producing antibodies that deliver reliable results for over 45 years. Our antibodies are manufactured and validated on-site to ensure target specificity and sensitivity. Validation is a continuous process at Bethyl, and we routinely evaluate new lots side-by-side with old lots to ensure lot-to-lot consistency. If a product doesn’t meet our standards, it doesn’t leave our facility. Interested in learning more about our validation process? Click here.

*Berglund, L., et al. A Genecentric Human Protein Atlas for Expression Profiles Based on Antibodies. Molecular & Cellular Proteomics, 7, 2019-27 (2009).

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Detection of human BRD4 (yellow) and Cytokeratin (red) in FFPE gastric carcinoma by IHC-IF. Antibody: Rabbit anti-BRD4 recombinant monoclonal [BL-149-2H5] (A700-004) and mouse anti-Cytokeratin monoclonal [AE1/AE3] (A500-019A). Secondary: DyLight® 650-conjugated goat anti-rabbit IgG (A120-201D5).


Detection of human BRD4 in formaldehyde-fixed HeLa cells by ICC-IF. Antibody: Rabbit anti-BRD4 recombinant monoclonal [BL-149-2H5] (A700-004). Secondary: DyLight® 550-conjugated goat anti-rabbit IgG cross-adsorbed (A120-201D3). Counterstain: Phalloidin Alexa Fluor® 488.


Detection of human BRD4 in FFPE ovarian carcinoma by IHC-IF (pseudo color). Antibody: Rabbit anti-BRD4 recombinant monoclonal [BL-149-2H5] (A700-004). Secondary: DyLight® 594-conjugated goat anti-rabbit IgG cross-adsorbed (A120-201D4). Counterstain: DAPI.


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1. Andrieu G, Belkina AC, Denis GV. 2016. Clinical trials for BET inhibitors run ahead of the science. Drug Discov Today Technol. Mar;19:45-50.

2. Devaiah BN, Gegonne A, Singer DS. 2016. Bromodomain 4: a cellular Swiss army knife. J Leukoc Biol. Oct;100(4):679–686.

3. Liu Z, Wang P, Chen H, Wold EA, Tian B, Brasier AR, Zhou J. 2017. Drug Discovery Targeting Bromodomain-Containing Protein 4. J Med Chem. Jun 8;60(11):4533-4558.

4. Najafova Z, Tirado-Magallanes R, Subramaniam M, Hossan T, Schmidt G, Nagarajan S, Baumgart SJ, Mishra VK, Bedi U, Hesse E, Knapp S, Hawse JR, Johnsen SA. 2016. BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire. Nucleic Acids Res. Jan 9;45(1):127–141.

5. Ocaña A, Nieto-Jiménez C, Pandiella A. 2017. BET inhibitors as novel therapeutic agents in breast cancer. Oncotarget Aug 1;8(41):71285-71291.

6. Wu SY, Chiang CM. 2007. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J Biol Chem. May 4;282(18):13141-13145.

7. Wu SY, Lee AY, Lai HT, Zhang H, Chiang CM. 2013. Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting. Mol Cell. Mar 7;49(5):843-857.

8. Yang Z, He N, Zhou Q. 2008. Brd4 Recruits P-TEFb to Chromosomes at Late Mitosis To Promote G1 Gene Expression and Cell Cycle Progression. Mol Cell Biol. Feb;28(3):967–976.