Genome-Wide Transcriptional Regulation Mediated by Biochemically Distinct SWI/SNF Complexes

Abstract

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.

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

“…AT-rich interactive domain-containing protein 1A and 1B (ARID1A, ARID1B) are mutually exclusive subunits of the chromatin remodeler complex SWI/SNF (Raab et al, 2015; Ryme et al, 2009). As part of the core SWI/SNF complex, ARID1A and ARID1B are conserved throughout metazoans and expressed across all human tissues.…”

Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes

“…ARID1A is the most commonly mutated SWI/SNF subunit in cancer, due to transcriptional functions that are non-redundant with ARID1B (21,22); however, cancers with deletions in ARID1A are dependent on ARID1B for viability (23) due to redundant, essential functions at enhancers (22). Additionally, homologous complexes can display transcriptionally antagonistic roles, as has been observed for ARID1A and ARID2-containing complexes at specific gene targets (8,20,24). Targeting specific SWI/SNF complexes has been proposed both for alleviating subunit-specific pathogenic function as well as to target essential redundant functions in cancers with mutations in the genes for specific subunits (25,26).…”

“…For example, ARID1A is high in embryonic stem cells while ARID1B is upregulated upon differentiation (19). The different BAF complexes containing these two paralogs share many of their genomic targets; however, they also bind unique genomic targets and deletions are non-synonymous for gene regulation (20). ARID1A is the most commonly mutated SWI/SNF subunit in cancer, due to transcriptional functions that are non-redundant with ARID1B (21,22); however, cancers with deletions in ARID1A are dependent on ARID1B for viability (23) due to redundant, essential functions at enhancers (22).…”

Disorders of Transcriptional Regulation: An Emerging Category of Multiple Malformation Syndromes

“…A previous study, using chromatin immunoprecipitation followed by massive [Raab et al, 2015]. Although ARID1A -encoded BAF250a and ARID1B -encoded BAF250b proteins do not coexist in a single complex, they bind to similar genomic locations.…”

“…BAF250a and BAF250b both bind close to transcriptional start sites of genes, as well as gene enhancer regions, suggesting the importance of the BAF complex in remodeling the promoter and enhancer regions of the chromatin structure ( fig. 4 b) [Raab et al, 2015]. However, the mechanism by which the BAF complex chromatin remodeler controls gene transcription remains to be fully understood.…”