BRD9, or Bromodomain-containing protein 9, is involved in fundamental cellular processes. This protein helps regulate how genes are expressed within cells, a process that underpins nearly all biological functions. Understanding BRD9 offers insights into basic cell biology and holds promise for addressing various health conditions.
Understanding BRD9
BRD9 is a protein encoded by the BRD9 gene in humans, belonging to a family of proteins that contain a specific structural feature called a bromodomain. This bromodomain acts as a specialized reader, recognizing and binding to acetylated lysine residues found on histone tails. Histones are proteins around which DNA is wrapped, forming a compact structure known as chromatin.
The interaction between BRD9’s bromodomain and these acetylated marks is important for its function in chromatin remodeling and gene regulation. Beyond its bromodomain, BRD9 also contains other domains that enable it to interact with additional proteins, facilitating its integration into larger cellular complexes. This allows BRD9 to precisely target specific regions of genetic material.
How BRD9 Regulates Gene Expression
BRD9 plays a part in the SWI/SNF chromatin remodeling complex, a group of proteins that modify chromatin structure. This complex uses energy from ATP to alter how DNA is packaged around histones, making genes more or less accessible for transcription. By changing the physical arrangement of DNA, the SWI/SNF complex helps determine which genes are turned on or off.
As a component of the non-canonical BAF (ncBAF) subcomplex of SWI/SNF, BRD9 contributes to this dynamic process. Its ability to bind to acetylated histones guides the complex to specific genomic locations. This directed targeting allows the ncBAF complex to either loosen or compact the chromatin structure, influencing whether genetic information can be read and converted into proteins.
BRD9-containing complexes are positioned at gene promoters and enhancers, regions that control gene activity. This precise localization ensures BRD9 can modulate transcriptional programs important for maintaining cell identity and proper cellular processes. Its role in regulating gene expression is essential for normal cell function.
BRD9’s Role in Cancer and Other Diseases
Disruptions in BRD9 function have been linked to the development and progression of various diseases, particularly certain types of cancer. In synovial sarcoma, a rare and aggressive cancer, BRD9 integrates into oncogenic SS18-SSX-containing BAF complexes. This integration is important for maintaining the aberrant gene expression programs that promote tumor cell survival and growth.
BRD9 has also been identified as a factor in acute myeloid leukemia (AML), where it is often overexpressed and is necessary for the survival of leukemic cells. Its suppression can lead to reduced cell proliferation and increased cell death in AML models. In malignant rhabdoid tumors, which result from mutations in the SMARCB1 gene (another SWI/SNF subunit), BRD9 becomes a specific vulnerability.
Beyond these cancers, BRD9 has been implicated in other conditions. For instance, in ovarian cancer, the bromodomain of BRD9 binds to acetylated RAD54, facilitating interactions necessary for homologous recombination repair, a process that can be exploited in therapy. BRD9’s role in chromatin remodeling also suggests its involvement in other conditions where gene expression is dysregulated.
Developing Therapies to Target BRD9
The involvement of BRD9 in various diseases, especially cancer, has made it an area of interest for therapeutic development. Researchers are exploring ways to target BRD9 with small molecule inhibitors designed to interfere with its function. These inhibitors work by binding to the bromodomain of the BRD9 protein, blocking its ability to recognize and interact with acetylated histones.
By preventing BRD9 from binding to its targets, these compounds can disrupt the aberrant gene expression patterns that drive disease progression. For example, compounds like I-BRD9, BI-7273, and BI-9564 have been developed as selective chemical probes for BRD9 inhibition. These inhibitors have shown promise in preclinical studies by modulating gene expression and inducing anti-tumor effects in models of cancers like acute myeloid leukemia and synovial sarcoma.
Developing therapies that specifically target BRD9 presents both opportunities and challenges. The goal is to create drugs that selectively interfere with BRD9’s activity without affecting other related proteins, which could lead to unwanted side effects. Continued research aims to refine these targeted approaches, potentially offering new treatment options for patients with BRD9-associated diseases.