Bromodomain-containing protein 4, BRD4, is a protein found within human cells that plays a role in various biological processes. It belongs to the BET (bromodomain and extraterminal domain) family, which also includes BRD2, BRD3, and BRDT. These proteins regulate gene expression, influencing cell growth and differentiation.
The Function of BRD4 in the Body
BRD4 operates as an “epigenetic reader” within the cell. Epigenetics refers to modifications that affect gene activity without altering the underlying DNA sequence, similar to instructions that tell genes when to turn on or off. BRD4 recognizes and attaches to specific chemical markers, known as acetylated lysine residues, found on histone proteins that package DNA. These acetylated histones are associated with active gene regions.
Once BRD4 binds to these acetylated histones, it acts as a scaffold, helping to assemble the molecular machinery needed for gene transcription. This includes recruiting factors like Positive Transcription Elongation Factor b (P-TEFb), which promotes the elongation of RNA polymerase II, a key enzyme in gene expression. This allows genes to be “read” and converted into proteins.
BRD4 contributes to fundamental cellular activities, including cell cycle progression and cell growth. It helps maintain consistent gene expression during cell division. BRD4’s presence on chromosomes during mitosis ensures proper gene expression across cell generations.
BRD4’s Role in Disease Development
In various diseases, particularly cancer, the normal function of BRD4 can become disrupted. This dysregulation often leads to BRD4 becoming hyperactive, which causes excessive transcription of genes that promote uncontrolled cell growth, known as oncogenes.
One example of a gene activated by BRD4 hyperactivity is c-MYC. The c-MYC oncogene is frequently overexpressed in many cancers, and its sustained expression is often driven by BRD4 activity. BRD4 can bind to the MYC promoter, maintaining its expression in cancer cells.
BRD4 is a driver in specific cancers, such as NUT midline carcinoma (NMC). This form of squamous cell cancer is characterized by a fusion protein, BRD4-NUT, which results from a chromosomal translocation. The BRD4-NUT fusion protein blocks normal cell differentiation and promotes tumor growth by forming hyperacetylated chromatin regions, or “megadomains,” which drive the transcription of underlying DNA, including oncogenes like c-MYC and TP63.
BRD4 also contributes to the pathogenesis of various leukemias and lymphomas, where its continuous activity is often necessary for oncogene expression.
Therapeutic Targeting of BRD4
Given its involvement in disease, BRD4 has become a target for medical intervention, leading to the development of BRD4 inhibitors, or more broadly, BET inhibitors. These small molecules interfere with BRD4’s function. They work by competitively binding to the bromodomain pockets within the BRD4 protein, where BRD4 normally recognizes and attaches to acetylated lysine residues on histones.
By occupying these binding pockets, BET inhibitors prevent BRD4 from interacting with acetylated histones and recruiting the necessary transcriptional machinery. This disruption leads to a downregulation of genes that promote cancer cell proliferation and survival.
BRD4 inhibitors are an area of cancer research and are currently being evaluated in numerous clinical trials. These trials explore their potential for treating both blood cancers, such as acute myeloid leukemia and lymphoma, and solid tumors. Compounds like JQ1, I-BET762, and OTX015 are examples of BET inhibitors under investigation.