Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy

Abstract

Subunits of mammalian SWI/SNF (mSWI/SNF, also called BAF) complexes have recently been implicated as tumor suppressors in a number of human malignancies. To understand the full extent of their involvement, we conducted a proteomic analysis of purified endogenous mSWI/SNF complexes. Our studies revealed several new dedicated, stable subunits not found in the yeast SWI/SNF complex including Bcl7a, b and c, Bcl11a and b, Brd9 and SS18. Incorporating these novel members, we determined the frequency of mSWI/SNF subunit mutations in recent exome- and whole-genome sequencing studies of primary human tumors. Surprisingly, mSWI/SNF subunits are mutated in 19.6% of all human tumors reported in 44 exome sequencing studies. Our analysis suggests that specific subunits protect against cancer in specific tissues. In addition, we find that mutations to more than one subunit, which we define as a type of compound heterozygosity, are prevalent in certain cancers. Our studies demonstrate that mSWI/SNF is the most frequently mutated chromatin-regulatory complex (CRC) in human cancer and that in contrast to other known tumor suppressors and oncogenes surveyed, mSWI/SNF is broadly mutated, similar to TP53. Thus, proper functioning of these polymorphic chromatin regulatory complexes may constitute a major mechanism of human tumor suppression.

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

“…BCL11A has been recently suggested by a proteomics study to be part of the BAF swi/snf chromatin remodeling complex (Kadoch et al, 2013). Dias et al (2016) showed differential expression of BAF swi/snf related genes in the hippocampus of Bcl11a haploinsufficient mice, suggesting that BCL11A is a BAFopathy gene.…”

“…The B‐cell lymphoma/leukemia 11A ( BCL11A ) gene encodes a C2H2 zinc‐finger transcription factor highly expressed in the brain and the adult erythroid lineage (Avram, Fields, Senawong, Topark‐Ngarm, & Leid, 2002; Leid et al, 2004; Nakamura et al, 2000), and is part of the murine BAF swi/snf chromatin remodeling complex (Kadoch et al, 2013). BCL11A has been shown to be a critical modulator of hemoglobin switching and HbF silencing (Basak et al, 2015; Funnell et al, 2015; Guda et al, 2015; Xu et al, 2013).…”

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers

“…Cancer genome sequencing efforts have revealed recurrent somatic mutations in several chromatin regulators, further implying a causal role for altered chromatin states in tumorigenesis (1). Indeed, one of the most significant findings from cancer genome profiling is the discovery of frequent mutations in various subunits of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex (2,3). The mSWI/SNF complexes consist of one of two mutually exclusive DNA-dependent ATPases, BRG1/ SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4) or BRM/ SMARCA2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 2), together with core and accessory subunits that function in mobilizing nucleosomes to regulate transcription, DNA replication and repair, and higher-order chromosome dynamics (4,5).…”

Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type–Specific Differences

“…It has only been previously implicated in lymphoma through the observation of complex rearrangements (44) and its overexpression was associated with Germinal Center (GC) phenotype in DLBCL (45). Interestingly, it is also a member of the SWI/SNF complex further highlighting the complex's importance (46). Mutations in BCL7A, SMARCA4 , and ARID1A were not observed to co-occur in either eBL or sBL.…”