The BAF complex in development and disease

Abstract

The ATP-dependent chromatin remodelling complex BAF (= mammalian SWI/SNF complex) is crucial for the regulation of gene expression and differentiation. In the course of evolution from yeast to mammals, the BAF complex evolved an immense complexity with a high number of subunits encoded by gene families. In this way, tissue-specific BAF function and regulation of development begin with the combinatorial assembly of distinct BAF complexes such as esBAF, npBAF and nBAF. Furthermore, whole-genome sequencing reveals the tremendous role BAF complex mutations have in both neurodevelopmental disorders and human malignancies. Therefore, gaining a more elaborate insight into how BAF complex assembly influences its function and which role distinct subunits play, will hopefully give rise to a better understanding of disease pathogenesis and ultimately to new treatments for many human diseases.

Keywords: BAF complex; Cancer; Chromatin remodelling; Epigenetic; Mammalian SWI/SNF complex; Neurodevelopmental disorders; Rhabdoid tumour; Synovial sarcoma.

Fig. 1

BAF complex subunit switches during mammalian development. BAF complex subunits undergo distinct switches during development to adapt to the requirements of more differentiated cell types. While the esBAF complex can only be found in embryonic stem cells and incorporates BRG1 as ATPase subunit, npBAF complexes can be found in neural progenitor cells and nBAF complexes first occur with mitotic exit. Colours are used to indicate the changes in subunit compositions. Most strikingly, npBAF can include BRM as alternative to BRG1, BAF250b as alternative to a, BAF60c as alternative to c and a BAF155::170 heterodimer to replace the BAF155::155 homodimer. nBAF-specific subunits are BAF53a, BAF45b/c and CREST. The ncBAF coexists with the esBAF complex in ESCs and has been shown to regulate naïve pluripotency by interacting with the transcription factors KLF4 and Sp5. It is characterised by the lack of many esBAF-specific subunits such as BAF250a, BAF47 and BAF57 and the incorporation of BRD9 and the ncBAF-specific subunit GLTSR1/L1. Until now, ncBAF complexes, apart from ESCs, could also be found in rhabdoid and synovial sarcoma tumour cell lines as well as in HEK293T cells

Fig. 2

The role of subunit mutations in developmental disorders. BAF subunit mutations have a high implication in human developmental disorders. The most frequent mutations and associations with human disease are summarised in this figure. Subunits being involved most frequently include the ATPase subunit BRM as well as the subunit BAF250b

Fig. 3

The role of subunit mutations in cancer. Mutations in BAF subunit do not only cause neurodevelopmental diseases but also have an important role in tumorigenesis. Genome-wide sequencing revealed that about 20% of human cancers show BAF subunit mutations; amongst the most frequently mutated subunits is BAF250a. Like BAF complex composition unique to some tissue types, many mutations have a “unique” pattern of malignancies they play a role in