Multiple positions within the SWI/SNF chromatin remodeling complex can be filled by mutually exclusive subunits. Inclusion or exclusion of these proteins defines many unique forms of SWI/SNF and has profound functional consequences. Often this complex is studied as a single entity within a particular cell type and we understand little about the functional relationship between these biochemically distinct forms of the remodeling complex. Here we examine the functional relationships among three complex-specific ARID (AT-Rich Interacting Domain) subunits using genome-wide chromatin immunoprecipitation, transcriptome analysis, and transcription factor binding maps. We find widespread overlap in transcriptional regulation and the genomic binding of distinct SWI/SNF complexes. ARID1B and ARID2 participate in wide-spread cooperation to repress hundreds of genes. Additionally, we find numerous examples of competition between ARID1A and another ARID, and validate that gene expression changes following loss of one ARID are dependent on the function of an alternative ARID. These distinct regulatory modalities are correlated with differential occupancy by transcription factors. Together, these data suggest that distinct SWI/SNF complexes dictate gene-specific transcription through functional interactions between the different forms of the SWI/SNF complex and associated co-factors. Most genes regulated by SWI/SNF are controlled by multiple biochemically distinct forms of the complex, and the overall expression of a gene is the product of the interaction between these different SWI/SNF complexes. The three mutually exclusive ARID family members are among the most frequently mutated chromatin regulators in cancer, and understanding the functional interactions and their role in transcriptional regulation provides an important foundation to understand their role in cancer.

Cancer is caused by germline and somatic mutations, which can share biological features such as amino acid change. However, integrated germline and somatic analysis remains uncommon. We present a framework that uses machine learning to learn features of recurrent somatic mutations to (1) predict somatic variants from tumor-only samples and (2) identify somatic-like germline variants for integrated analysis of tumor-normal DNA. Using data from 1769 patients from seven cancer types (bladder, glioblastoma, low-grade glioma, lung, melanoma, stomach, and pediatric glioma), we show that “somatic-like” germline variants are enriched for autosomal-dominant cancer-predisposition genes (p < 4.35 × 10−15), including TP53. Our framework identifies germline and somatic nonsense variants in BRCA2 and other Fanconi anemia genes in 11% (11/100) of bladder cancer cases, suggesting a potential genetic predisposition in these patients. The bladder carcinoma patients with Fanconi anemia nonsense variants display a BRCA-deficiency somatic mutation signature, suggesting treatment targeted to DNA repair.

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Background: We often consider the SWI/SNF complex as a single entity with a single function in a particular cell type. This model ignores that multiple positions within the SWI/SNF chromatin remodeling complex can be filled by mutually exclusive subunits. Inclusion or exclusion of such subunits gives rise to an array of biochemically distinct chromatin remodeling complexes, some of which have profound functional consequences on gene regulation and differentiation. Here, we examine the functional relationships among three complex-specific ARID (AT-Rich Interacting Domain) subunits of the SWI/SNF complex in a human hepatocellular carcinoma cell line using ChIP-seq, RNA-seq, and public data on transcription factor binding. Results: Using RNAi directed at each of the three subunits, we identify widespread overlap in transcriptional regulation mediated by SWI/SNF. The ARID subunits are commonly bound together at the promoters of active genes, with more variable binding associated with distal regulatory elements. ARID1B and ARID2 cooperate to repress the expression of hundreds of genes. Additionally, we identify many examples of competitive interactions between ARID1A and ARID1B or ARID2, and show that gene expression changes following loss of one ARID are dependent on the function of an alternative ARID. These distinct regulatory modalities are correlated with differential occupancy by transcription factors. Together these data suggest distinct SWI/SNF complexes dictate gene-specific transcription through interactions between different forms of SWI/SNF and specific co-factors. The ARID subunits are among the most frequently mutated chromatin regulators in cancer. Understanding the functional relationship between distinct forms of the complex is a necessary first step for identifying their potentially unique roles in oncogenesis. Citation Format: Jesse R. Raab, Samuel Resnick, Terry Magnuson. Transcriptional regulation mediated by biochemically distinct forms of SWI/SNF. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr PR02.