TY - JOUR
T1 - SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation
AU - Wang, Xiaofeng
AU - Lee, Ryan S.
AU - Alver, Burak H.
AU - Haswell, Jeffrey R.
AU - Wang, Su
AU - Mieczkowski, Jakub
AU - Drier, Yotam
AU - Gillespie, Shawn M.
AU - Archer, Tenley C.
AU - Wu, Jennifer N.
AU - Tzvetkov, Evgeni P.
AU - Troisi, Emma C.
AU - Pomeroy, Scott L.
AU - Biegel, Jaclyn A.
AU - Tolstorukov, Michael Y.
AU - Bernstein, Bradley E.
AU - Park, Peter J.
AU - Roberts, Charles W.M.
N1 - Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature.
PY - 2017/1/31
Y1 - 2017/1/31
N2 - SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here we show that, despite having indistinguishable mutational landscapes, human rhabdoid tumors exhibit distinct enhancer H3K27ac signatures, which identify 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 by all subtypes, such as SPRY1, and other lineage-specific super-enhancers, such as SOX2 in brain-derived rhabdoid tumors. Taken together, our findings identify a new chromatin-based epigenetic mechanism underlying the tumor-suppressive activity of SMARCB1.
AB - SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here we show that, despite having indistinguishable mutational landscapes, human rhabdoid tumors exhibit distinct enhancer H3K27ac signatures, which identify 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 by all subtypes, such as SPRY1, and other lineage-specific super-enhancers, such as SOX2 in brain-derived rhabdoid tumors. Taken together, our findings identify a new chromatin-based epigenetic mechanism underlying the tumor-suppressive activity of SMARCB1.
UR - http://www.scopus.com/inward/record.url?scp=85003875989&partnerID=8YFLogxK
U2 - 10.1038/ng.3746
DO - 10.1038/ng.3746
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C2 - 27941797
AN - SCOPUS:85003875989
SN - 1061-4036
VL - 49
SP - 289
EP - 295
JO - Nature Genetics
JF - Nature Genetics
IS - 2
ER -
