SMARCB1 is required for widespread BAF complex–mediated activation of enhancers and bivalent promoters

Abstract

Perturbations to mammalian SWI/SNF (BAF) complexes contribute to over 20% of human cancers, with driving roles first identified in malignant rhabdoid tumor (MRT), an aggressive pediatric cancer characterized by biallelic inactivation of the core BAF complex subunit SMARCB1 (BAF47). However, the mechanism by which this alteration contributes to tumorigenesis remains poorly understood. We find that BAF47 loss destabilizes BAF complexes on chromatin, absent significant changes in intra-complex integrity. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in increased genome-wide BAF complex occupancy, facilitating widespread enhancer activation and opposition of polycomb-mediated repression at bivalent promoters. We demonstrate differential regulation by BAF and PBAF complexes at enhancers and promoters, respectively, suggesting distinct functions of each complex which are perturbed upon BAF47 loss. Our results demonstrate collaborative mechanisms of mSWI/SNF-mediated gene activation, identifying functions that are coopted or abated to drive human cancers and developmental disorders.

ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to PARP inhibition in lung cancer

“…In terms of the molecular mechanisms behind this regulation, we show that ARID2-deficiency is associated with profound chromatin structural changes. Our results prove that ARID2 is essential to keep an open chromatin structure in enhancer regions in agreement with an important role of different SWI/SNF members in regulating enhancer activity 39,40 . One of these ARID2-dependent enhancers regulates MTSS1 expression that, consequently, shows a significant downregulation in ARID2-deficient cells.…”

The structure of INI1/hSNF5 RPT1 and its interactions with the c‐MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex

“…Recently several studies have shown that loss of PPIs that are mediated by INI1 is one of the major factors contributing to oncogenesis in malignant rhabdoid tumors [36,37]. Most of the PPIs made by this subunit have been mapped to the repeats (1 and 2) [23], and consistent with this the structure of RPT1 reveals a fold that is an established PPI motif.…”

Inhibition of MYC attenuates tumor cell self‐renewal and promotes senescence in SMARCB1‐deficient Group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo

“…Recent transcriptomic analysis suggest that that SMARCB1 deletion results in significant plasticity of ATRT cells . Functionally, SMARCB1 deletion results in aberrant SWI/SNF protein complexes that occupy enhancers and SE, thereby regulating differential genomic programs between pluripotency, cell identity and differentiation. We hypothesized that targeting molecular pathways that mediate the tumorigenesis driven by SMARCB1 deletions maybe a promising avenue for new therapeutic development.…”

“…Recent functional studies demonstrate that genetic deficiencies in the SWI/SNF complex lead to assembly of aberrant complexes and differential occupancy of super‐enhancers (SE) . Furthermore, SMARCB1 is key for SWI/SNF complex occupancy at enhancers to activate bivalent promoters . How differential occupancy at SE results in transcriptional plasticity and cell malignancy is unclear.…”

“…9 Furthermore, SMARCB1 is key for SWI/SNF complex occupancy at enhancers to activate bivalent promoters. 10 How differential occupancy at SE results in transcriptional plasticity and cell malignancy is unclear. Wang et al suggest that aberrant SWI/SNF complexes abnormally activate pluripotency transcription factors such as SALL4 and SOX2 through their SE.…”