SMARCB1 Mutations Disrupt Enhancer Activity in Rhabdoid Tumors

Loss of the SWI/SNF chromatin-remodeling complex subunit SMARCB1 drives rhabdoid tumors, which otherwise have few genetic alterations. To determine how mutations in this SWI/SNF subunit drive oncogenesis, Wang, Lee, Alver, and colleagues characterized the chromatin landscape of 12 rhabdoid tumors as well as 3 rhabdoid tumor cell lines with and without SMARCB1 reexpression and murine embryonic fibroblasts conditional for SMARCB1. Despite their low mutation rates, the tumors exhibited largely dissimilar enhancer profiles with lineage-specific enhancers found in rhabdoid tumors from different tissues. Further, superenhancers were identified near genes regulating neural development, including SOX2, FZD1, and FZD3 in brain-derived tumors, and a superenhancer proximal to TBX2, a regulator of kidney development, in kidney-derived tumors. Loss of SMARCB1 destabilized the SWI/SNF complex and reduced the occupancy of SWI/SNF at typical enhancers. Loss of SMARCB1 decreased SWI/SNF complex occupancy at enhancers associated with development and differentiation, and downregulated genes involved in tissue-specific differentiation. Consistent with these findings, SMARCB1 loss disrupted expression of most SWI/SNF-regulated genes. In contrast to the effect of SMARCB1 loss at typical enhancers, SMARCB1 loss had little effect on the binding of SWI/SNF at superenhancers because the residual SWI/SNF complexes bound preferentially to superenhancers over typical enhancers. Moreover, the retained superenhancers were required for rhabdoid tumor survival. Collectively, these results suggest an epigenetic mechanism by which SMARCB1 mutations may promote oncogenesis by retaining SWI/SNF occupancy at superenhancers required for rhabdoid tumor survival while disrupting SWI/SNF binding at typical enhancers required for tissue-specific development and differentiation. Further, the identification of essential genes regulated by superenhancers in rhabdoid tumors may indicate putative therapeutic targets.

Wang X, Lee RS, Alver BH, Haswell JR, Wang S, Mieczkowski J, et al. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation. Nat Genet 2016 Dec 12 [Epub ahead of print].