The BAF complex, also known as SWI/SNF, is a multi-protein machine operating within our cells. This complex functions like a master key for the genetic code, controlling which genes are turned on or off at specific times. It regulates gene expression by making certain parts of our DNA accessible for cellular processes.
The Role in Gene Accessibility
Our DNA is packaged inside the cell’s nucleus, wrapped around proteins called histones, forming nucleosomes. This compact arrangement, called chromatin, allows DNA to fit into a tiny space. However, this tight packaging also makes most genes inaccessible to cellular machinery.
The BAF complex remodels chromatin. Using energy from ATP hydrolysis, the complex can slide, eject, or restructure nucleosomes. This action effectively unwraps specific sections of DNA, much like unzipping a tightly packed suitcase to access its contents. By exposing these genes, the BAF complex makes them available for transcription, allowing the cell to read their instructions.
Composition and Versatility
The BAF complex is a multi-protein assembly composed of various subunits. In mammals, 29 genes encode protein subunits that combine in various ways to form the complex. The combination of these 10 to 15 subunits can vary depending on the cell type, developmental stage, or cellular signals.
This modular nature creates different BAF complex subtypes: canonical BAF (cBAF), Polybromo-associated BAF (pBAF), and non-canonical BAF (ncBAF), also known as GLTSCR-associated BAF (gBAF). Each subtype has a common core but includes unique subunits that define its structure and function. For instance, cBAF often acts at promoters and enhancers to open chromatin, while pBAF can be found along gene bodies and is linked to both transcriptional activation and repression. This ability to swap subunits allows the BAF complex to target distinct genes and perform specialized tasks in different cellular contexts.
Function in Cellular Development
The BAF complex’s regulation of gene expression is fundamental for cellular development, particularly during cell differentiation. This is the process where unspecialized stem cells transform into specialized cell types, such as neurons, muscle cells, or skin cells. These transformations require a coordinated sequence of turning specific genes on and off.
The BAF complex guides cell fate decisions by remodeling chromatin at key developmental genes. For example, it helps maintain neuronal progenitors in a stem cell state and regulates the balance between proliferation and differentiation in early brain development. Its ability to promote chromatin accessibility at target loci, including genes for mesoderm- and ectoderm-derived lineages, underscores its importance in tissue formation and regeneration.
Connection to Cancer and Neurodevelopmental Disorders
Malfunctions in the BAF complex, often due to genetic mutations, are frequently observed in human diseases. Mutations in BAF complex subunits are found in over 20% of human cancers, making them among the most frequently mutated molecular entities after TP53. If the BAF complex can no longer properly silence genes that promote uncontrolled cell growth, it can lead to unchecked cell division and tumor formation.
Specific subunits, such as ARID1A, SMARCB1, and SMARCA4, are known tumor suppressors, and their alterations are common in various malignancies including hepatoblastoma and synovial sarcoma. For instance, the SS18-SSX fusion protein in synovial sarcoma can hijack the BAF complex, re-targeting it to new sites on chromatin and increasing accessibility at those locations, including normally repressed polycomb sites.
Beyond cancer, BAF complex gene mutations are also linked to several neurodevelopmental disorders. For example, Coffin-Siris syndrome is associated with pathogenic variants in BAF complex genes like ARID1A, ARID1B, SMARCB1, SMARCA4, and SMARCE1. These mutations disrupt the precise gene regulation needed for proper brain development, leading to conditions characterized by intellectual disability and other congenital anomalies. The frequent involvement of BAF complex mutations in both cancer and neurodevelopmental disorders highlights its broad influence on human health.