Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics.

Evolution of the yeast SWI/SNF complexes to the fly BAP and vertebrate BAF complexes.The figure depicts the subunit structure of these related complexes over the last 500 million years of evolutionary history. Colors are used to indicate homology. The development of multicellularity and the need to repress most genes is coupled with the appearance of polycomb-mediated repression, histone H1, and major changes in the subunit structure of SWI/SNF in its transition to BAP complexes in flies. The emergence of vertebrates, appearance of a much larger genome, DNA methylation, and vertebrate complexity is accompanied by another transition in subunit structure and combinatorial assembly. Finally, with the emergence of a complex nervous system, four new neuron-specific subunits enter the complex and are essential for dendritic morphogenesis, synaptogenesis, and connectivity within the nervous system.

BAF complexes change their subunit composition during development.Murine ES cells have a specific subunit composition (esBAF) that is apparently not found in other cell types to date. Overexpression of the esBAF subunits can facilitate induction of pluripotent cells from fibroblasts. In neural stem cells that line the developing neural tube, a second form of BAF complexes is found that again is distinguished, but not by subunits expressed only in neural progenitors, but rather an assembly that appears to be found only in neural progenitors. In postmitotic neurons, three subunits found only in neurons are present in complexes immediately after mitotic exit. These include BAF53b, BAF45b, and CREST. In cardiac progenitors, complexes are distinguished by the expression of BAF60c, whereas in hematopoietic stem cells, complexes contain Brm, but not Brg, and BAF60b and BAF60c, but not BAF60a, and Bcl7b and Bcl7c, but not Bcl7a.

BAF subunits are frequently mutated in human cancer.Left: The subunit composition of the BAF complex is shown with the cancers containing frequent mutations in specific BAF subunits. The general pattern that emerges is that specific subunits protect against cancer in specific tissues. Right: The polybromo containing the pBAF complex with known specific subunits: BAF180 (polybromo PBRM1), BAF200 (ARID2), BAF45a (PHF10), and BRD7.

BAF complexes can be oncogenes or tumor suppressors.Top: The fusion of the SS18 gene to the SSX gene adds 78 amino acids (aa) of SSX to SS18, giving a fusion protein that evicts wild-type SS18 as well as BAF47 (hSNF5). The resulting oncogenic BAF complex is then targeted to new loci over the genome, such as Sox2, through a transcription factor–independent mechanism to genes that are drivers of proliferation. At these genes, it robustly evicts polycomb by unknown mechanisms leading to activation of genes such as Sox2 that can drive proliferation. Bottom: In the rare rhabdoid sarcoma of young children, the biallelic loss of BAF47 leads to a complex with defective ability to evict polycomb at loci such as Ink4a that repress proliferation. Cells are then transformed without additional mutations. Note that these mechanisms are brought about by a gain of ability to evict polycomb versus a loss of ability to evict polycomb. Both mechanisms are probably distinct from the more common cancers produced in older individuals with mutations in other subunits that compromise the ability to allow TopoII function, as shown in Fig. 6.

Mutations in BAF complexes and polycomb complexes affect the balance between these two major genomic chromatin regulators.(A) In cells without defined mutations in genes encoding BAF complex subunits, BAF and polycomb complexes oppose one another to facilitate the coordinate regulation of gene expression. (B) Upon loss-of-function (LOF) mutations, such as biallelic inactivation of hSNF5 (BAF47) in MRTs, BAF complexes lose the ability to oppose polycomb, resulting in higher overall levels and repressive histone mark placement genome-wide. (C) In specific gain-of-function (GOF) settings, such as human synovial sarcomas that contain the SS18-SSX oncogenic fusion protein, BAF complexes appear to oppose polycomb complexes at key oncogenic loci.

Mechanism of synergy between BAF and TopoII and its loss in common cancers bearing BAF subunit mutations.On the left is the normal mechanism of TopoII function. On the right is the mechanism when an oncogenic BAF subunit is mutated. BAF is necessary for binding of TopoIIa to DNA at 11,000 of 16,000 sites over the genome. When TopoII fails, it leads to the inability to resolve tangled DNA and the production of anaphase bridges, as shown in the inset. The mechanism by which DNA is repaired after possibly being cleaved in the cytoplasm by cytoplasmic DNase is unclear, but might be error-prone and lead to an accumulation of mutations.