SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation

Abstract

SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex1,2, is inactivated in nearly all pediatric rhabdoid tumors3–5. These aggressive cancers are among the most genomically stable6–8, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human rhabdoid tumors show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting – markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers, like SOX2 in brain-derived rhabdoid tumors. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.

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

“…SMARCB1 deletion results in reduced occupancy of SWI/SNF complex at standard enhancers of differentiation‐specific genes and occupancy at SE of genes associated with lineage specificity and pluripotency . Our data show that MYC chromatin occupancy at differentiation and pluripotency gene promoters is altered in SMARCB1 deleted cells (Fig.…”

“…Wang et al . suggest that aberrant SWI/SNF complexes abnormally activate pluripotency transcription factors such as SALL4 and SOX2 through their SE . Here we show that another pluripotency‐associated transcription factor, the c‐ MYC oncogene (henceforth MYC ), is a critical regulator of ATRT malignant behavior in the context of SMARCB1 deletion.…”

Sarcoma–The standard-bearer in cancer discovery

“…The SWI/SNF complex facilitates the unwinding of heterochromatin through an ATP-dependent manner. These complexes are impaired in their targeting to DNA when SMARCB1 is absent resulting in a loss of the complex at enhancers that maintain differentiation and remaining at super-enhancers that promote survival (Wang et al, 2017). These studies have demonstrated how crucial epigenetic integrity is at enhancer regions and may point to universal epigenetic means of reversing the state of differentiation, which is often associated with malignant disease.…”

SWI/SNF complex in cancer

“…To investigate the impact of SMARCB1 inactivation on SWI/SNF complex assembly and targeting, Roberts, Bernstein, Park and colleagues 5 examined the genome-wide localization of SWI/SNF complex in SMARCB1-wildtype and deficient rhabdoid tumors and cell lines. In addition to gene promoters, they found that a substantial portion of SWI/SNF complexes were recruited to enhancers and so-called ‘super-enhancers’ (clusters of active enhancers) in SMARCB1-wildtype cells.…”

“…Mutations, translocations and deletions involving various subunits of SWI/SNF complex were found in ∼20% of human tumors, making the complex as one of the most commonly affected target in cancer 4 . In this issue, four research articles offer novel insights into the mechanisms by which SWI/SNF complex alterations lead to defective complex assembly and recruitment, abnormal gene silencing and tumor development 5-8 . Importantly, these mechanisms help explain the preclinical efficacies of several therapeutic approaches developed to target SWI/SNF-mutated tumors.…”