The SWI/SNF complex, known as the BAF (BRG1/BRM-associated factor) complex in mammals is a chromatin remodeling complex with multiple subunits that regulate gene expression by altering chromatin accessibility and DNA access for transcription factors. BAF complex remodels nucleosomes through ATP hydrolysis mediated by its catalytic subunits BRG1 (SMARCA4) or BRM (SMARCA2).
The BAF complex exists in subtypes, canonical BAF (cBAF), BAFE (PBAF), and non-canonical BAF (ncBAF), each defined by unique subunit compositions that lead them to have specific biological functions. Mutations, including the loss of function mutations, in specific subunits have been a driving factor in various human diseases, most notably cancer, making BAF complexes integral in current molecular biology and research pertaining to biomedicine.
About 20% of patients with different forms of cancer had mutations in at least one BAF complex member. In particular, these include breast cancers related to mutations in ARID1A/B, PBRM1, and ARID2, endometriosis-associated ovarian cancers caused by mutations in ARID1A, and renal medullary carcinomas characterized by loss of SMARCB1. Additionally, both diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma are subtypes of non-Hodgkin lymphoma originating from germinal center B cells; while DLBCL is the most common, Burkitt lymphoma is the most aggressive and clinically significant. Burkitt lymphoma, in particular, is frequently linked to mutations in ARID1A and SMARCA4.
Structure and subunits The BAF complex is composed of three main modules. Among these, the ATPase motor module is the driving force behind chromatin remodeling. This module uses the energy obtained from ATP hydrolysis to move nucleosomes along the DNA. The core module, including ARID1A and SMARCC subunits, structures the complex and facilitates interactions with the other modules. The Actin-Related Protein module, which connects these two modules, enhances the structural integrity of the complex and ensures proper transmission of mechanical forces within it. Different combinations of the subunits that make up these modules determine the functional diversity of the complex, leading to the formation of subcomplexes such as cBAF, PBAF, and ncBAF (Table 1). Therefore, the structure of the BAF complex enables cell-specific genetic responses through specific dynamic interactions between modules and variability in subunit composition. cBAF: The cBAF complex, which is the most common among the others, plays a role in the initiation of gene expression. It functions primarily at enhancer regions, controlling developmental processes and playing a critical role in cell differentiation. PBAF: PBAF contributes to the maintenance of gene transcription. It is typically localized at active promoter regions and also functions as a tumor suppressor in certain contexts. ncBAF: Although it also acts at enhancer regions like cBAF, unlike the other two complex types, ncBAF has a distinct structure. It is known to regulate cell type-specific gene expression. Moreover, the unique composition of the ncBAF complex (i.e. Bromodomain-containing protein 9 -BRD9- subunit) makes it an attractive target for drug development efforts.
The three forms of the BAF complex (Figure 1) have different combinations of parts that show how each one works in a specific way. For example, the ncBAF includes SS18, GLTSCR1/1L, and BRD9; cBAF has ARID1A/B, DPF1/2/3, and SS18. SS18 is shared among these two complexes but not with PBAF. On the other hand, PBAF includes PHF10, ARID2, BRD7, and PBRM1, which are unique to it. Meanwhile, ACTL6, β-actin, BCL7A/B/C, SMARCA2/4, SMARCD1/2/3, SMARCB1, SMARCE1, and SMARCC1/2 are shared across all three complex types (Table 1).
Table 1. Subunit compositions of mammalian BAF complexes Subunit TypencBAFcBAFPBAFSharedACTL6, β-actin, BCL7A/B/C, SMARCA2/4, SMARCD1/2/3, SMARCB1, SMARCE1, SMARCC1/2SpecificBRD9, GLTSCR1/1L, SS18ARID1A/B, DPF1/2/3, SS18PHF10, ARID2, BRD7, PBRM1
Biochemical mechanisms of BAF complex remodeling
Many remodeling enzymes utilize the energy derived from ATP hydrolysis to shift DNA along nucleosomes through its ATP-dependent DNA translocase activity. In BAF complexes, BGR1 and BRM are the catalytic subunits. After BRG1/BRM binds to the nucleosome through mechanisms such as twist diffusion and loop recapture, it applies a mechanical force to the DNA, loosening the interactions between the histone octamers and the DNA. In this way, the opened regions of DNA become accessible to various transcription factors, RNA polymerase II, and other regulatory proteins. The subunits of this complex recognize specific histone modifications and DNA sequences: bromodomain-containing subunits (BRG1, BRM, PBRM1, BRD7/9) bind to acetylated histones, while PHD fingers (e.g., DPF2/DPF3) specifically recognize acetylated H3 histone tails. Additionally, the ARID1A/B and ARID2 subunits bind to AT-rich DNA regions. What distinguishes the BAF complex from other chromatin remodeling complexes is its ability not only to shift nucleosomes but also to completely evict histone octamers when necessary. Additionally, the BAF complex functions in balance with Polycomb complexes, which mediate gene repression through mechanisms such as H3K27 methylation. When BAF function is impaired while Polycomb activity remains intact, gene silencing persists, leading to the repression of tumor suppressor genes and potentially contributing to oncogenic outcomes.
The BAF complex in cells plays roles in various processes such as cell differentiation, development, and maintenance of viability. Specifically, subunits like BRG1 and SMARCC1 maintain pluripotency, subunit switching in neuronal cells enables neuronal differentiation, and it regulates tissue-specific gene expression in muscle and heart. In adult cells, the complex functions in DNA damage repair, cell cycle control, and preservation of cell identity.
Roles in disease
The mammalian BAF complex is disrupted frequently in human disease, and mutations in the subunits of the BAF complex have been responsible for causing roughly 20% of all human tumors. Subunits of the BAF complex like ARID1A, SMARCB1, SMARCA4, PBRM1, and ARID2 are considered to be tumor suppressors and are often affected by loss of function mutations across cancers.
Because the BAF complex is modular, phenotypes in disease can indicate which subunit is altered. Different subunits direct targeting and activity at enhancers, so mutations in different subunits have different methods, impact on tumorigenesis, and therapeutic vulnerabilities. Through destabilizing the cBAF complex and the accessibility of enhancers, ARID1A, for instance, is mutated in nearly half of all ovarian clear-cell and endometrioid carcinomas and is associated with loss-of-function defects that occur early in the progression of malignant transformation of endometriosis. The majority of ARID1A mutations are truncating, leading to the protein being lost; however, without ARID1A, cBAF shifts to using ARID1B, which has far less abundance at enhancers, all the while decreasing the accessibility of the chromatin.
Beyond defects that target enhancers, the loss of structural subunits removes the platform that recruits BRG1/BRM onto the chromatin, diminishing remodeling at genes involved in checkpoint and differentiation. Particularly, SMARCB1 is biallelically inactivated in nearly all malignant rhabdoid tumors, which demonstrates one of the first genetic links between loss of the BAF complex and severe pediatric cancers. SMARCA4 loss of function can disable the very ATPase involved in remodeling in BAF and cause small cell carcinoma of the ovary, hypercalcemic type, while recurring as mutations in non-small cell lung cancers, where the restriction of nucleosome mobility can silence the existing tumor suppressor genes.
Carcinogenic potential is not restricted to the cBAF complex, however, since over 40% of clear-cell renal carcinomas are characterized by PBRM1 deletions/truncations. The loss of bromodomain in PBRM1 reduces the ability to recognize acetylated histones, causing a change in gene expression. Although they are less frequent, ARID2 mutations, also disrupting PBAF-derived chromatin regulation, play a part in hepatocellular carcinoma development like that of hepatitis C through defectively recruiting chromatin remodelers to the tumor suppressors that restrain uncontrolled proliferation.
Germline disruption of the BAF complex's chromatin-remodeling specific complexes is a central cause of Mendelian neurodevelopmental disease. Clinically, ARID1B loss-of-function mutations are present in nearly two-thirds of cases of the Coffin–Siris spectrum, impeding proper intellectual development, language delays in expression, increased seizure susceptibility, and frequent midline neurological implications such as corpus-callosal defects. Other subunits of the BAF complex, including ARID1A, SMARCB1, SMARCE1, and SMARCA4, can also cause Coffin–Siris–like phenotypes when mutated, underscoring the specific roles of this remodeling machinery in human neural development. By contrast, Nicolaides–Baraitser syndrome is caused primarily by de novo missense variants in SMARCA2, which produce severe intellectual disability, distal-limb anomalies, and sparse hair.
Role of ARID1A as tumor suppressor ARID1A, as part of cBAF, possesses an essential tumor-suppressing activity that is frequently mutated in various human cancers, including in 46–57% of ovarian clear cell carcinomas and 30% of endometrioid carcinomas as well as in prostate, breast, pancreatic and more cancers. One of ARID1A's several pivotal functions is its ability to direct cBAF to the enhancers, promoting oncogenesis through faulty genomic regulation. Although ARID1A loss on its own has been shown as insufficient for tumorigenesis, it can induce ovarian adenocarcinomas when paired with PIK3CA activation, after having released IL-6 and activated NF-κB. This cooperation between PI3K and ARID1A is prominent because PIK3CA supplies proliferation of cells and the loss of ARID1A changes the interactions between enhancers and inflammation within the cells, creating a feed-forward loop between IL-6, STAT3 and NFkB. Namely, when ARID1A and PIK3CA are mutated, there is a promotion of IL-6 and activation of STAT3 because of the newly established inflammatory cytokine loop. In this signalling state, the interaction increases between the tumor and the environment surrounding it, recruiting pro-tumor myeloid cells.
Because ARID1A loss with PIK3CA activation increases PI3K–AKT signalling, EZH2 blockade that restores the endogenous inhibitor PIK3IP1 provides a PIK3IP1-dependent vulnerability in ARID1A-mutant systems. Through reactivating tumor suppressors like PIK3IP1, which can represent a potential therapeutic strategy due to its ability to limit PI3K–AKT signalling, EZH2 inhibition is able to target specifically cancer cells that are ARID1A-mutant tumors.
ARID1A deficiency also limits interferon signaling, which is critical in the human immune response, as well as invasion of CD8+ T-cells. Thus, the cell can pass through most immune checkpoints because the loss of ARID1A leads to closing antigen-related enhancers. In prostate tumours, ARID1A deletion combines with loss of PTEN to increase the amount of tumor growth as well as PMN-MDSCs infiltration through continued NF-κB activation. Inflammatory IKKβ signalling phosphorylates ARID1A, degrading the protein as well as silencing of A20 enhancer activity, which further boosts suppression from immune NF-κB, creating a feedback loop of NF-κB.
SMARCB1 and rhabdoid tumors