Brahma-related gene 1 (BRG1), also known as SMARCA4, is a protein that helps manage the vast amount of genetic information stored in our DNA. Like a librarian for a genetic library, BRG1 organizes DNA to ensure the correct genes are accessible for reading at appropriate times. This precise regulation of gene activity is fundamental for every cell.
The Role of BRG1 in Gene Expression
Our DNA is not freely floating within cells; instead, it is tightly packaged around specialized proteins called histones, forming a complex structure known as chromatin. This packaging influences whether genes can be accessed and read. BRG1 serves as a core component of a larger assembly called the SWI/SNF complex, which acts as a molecular machine. This complex utilizes energy derived from ATP, the cell’s energy currency, to physically rearrange the chromatin structure.
The SWI/SNF complex, powered by BRG1, can slide or eject histones along the DNA. This action unpacks specific DNA regions, making genes accessible to cellular machinery and turning gene expression “on.” Conversely, BRG1 can also facilitate DNA repackaging, effectively turning gene expression “off” by making regions less accessible.
BRG1 as a Tumor Suppressor
A tumor suppressor gene functions like a brake, preventing cells from growing and dividing uncontrollably. When the gene that produces BRG1, SMARCA4, undergoes mutations or is lost, this crucial “braking” function can be impaired. Such an impairment allows cells to proliferate without the normal regulatory checks, a characteristic feature of cancer.
BRG1’s proper function regulates cell growth, division, and maturation. Its inactivation disrupts these processes, contributing to the unchecked cell proliferation seen in malignant transformations, thus impairing its role in maintaining cellular control.
Conditions Associated with BRG1 Mutations
Mutations or the loss of BRG1/SMARCA4 are strongly linked to several specific types of cancer. One such condition is Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT), a rare and aggressive ovarian cancer. Inactivating mutations in SMARCA4, often accompanied by the complete loss of BRG1 protein, are identified in the majority of SCCOHT cases, making this loss a defining characteristic.
BRG1 alterations are also observed in certain non-small cell lung cancers (NSCLC), where primary tumors often show reduced BRG1 expression. The loss of BRG1 in NSCLC cells can lead to increased tumor aggressiveness by altering chromatin organization and gene expression. Additionally, atypical teratoid/rhabdoid tumors (AT/RT), aggressive pediatric brain tumors, are frequently characterized by inactivating mutations in SMARCA4. In these cancers, the absence of functional BRG1 contributes to uncontrolled cell growth.
Importance in Normal Development
Beyond its role in preventing abnormal cell growth, BRG1 performs a fundamental function during embryonic development. Its capacity to precisely activate and deactivate specific genes is necessary for guiding cells to differentiate and form various tissues and organs. BRG1 is expressed at high levels throughout post-implantation development, underscoring its broad influence.
Studies show that the complete absence of BRG1 in mice results in embryonic death. This lethality is linked to increased programmed cell death and growth retardation in the early embryo. These findings emphasize that BRG1 is necessary for the proper formation and organization of a healthy organism.
Clinical and Therapeutic Implications
Knowledge about BRG1 has practical applications in cancer diagnostics and the development of new treatments. For diagnostics, doctors can test for SMARCA4 mutations or the loss of BRG1 protein in tumor samples. This testing helps diagnose certain cancers, such as SCCOHT, and informs treatment decisions where BRG1 loss is a defining feature. Immunohistochemical analysis is often used to detect the absence of BRG1 protein.
In therapeutics, research focuses on strategies to target cancers that have lost BRG1 function. One promising approach involves synthetic lethality, where the combined loss of two specific genes is lethal to a cell, but the loss of either gene alone is not. BRG1-deficient cancers can become dependent on SMARCA2 for survival. Researchers are investigating drugs, such as SMARCA2 degraders, that specifically target SMARCA2, aiming to selectively eliminate BRG1-deficient cancer cells while sparing healthy cells.