Cancer researchers have been SNFing around the role of the SWI/SNF complex for a long time. By SWItching to a ChIP-seq approach, novel details about how biallelic loss of a key gene promotes a cancerous epigenome have been uncovered. SWI/SNF (or BAF) is a chromatin remodeling complex and a key regulator of early development that is perturbed in many cancers. SMARCB1, which encodes a complex stabilizing member of SWI/SNF, is mutated in 95% of atypical teratoid rhabdoid tumors (ATRTs). ATRTs are highly aggressive brain tumors arising in young children and infants. These patients have a very poor prognosis; safe and effective therapeutic approaches are need.
The lab of Marcel Kool at the German Cancer Research Center (Heidelberg, Germany) has long been studying ATRTs genomics. In their previous work, they found that ATRTs could be divided into three molecular subgroups, each characterized by distinct pathways aberrantly regulated. However, the comprehensive epigenetic landscape of ATRTs had not yet been studied and was of particular importance given the role of SMARCAB1 in chromatin remodeling/epigenetic regulation. To aid in their tackling of chromatin’s complex challenges, the talented team utilized Active Motif’s ChIP-seq services to examine histone marks associated with active (H3K27ac, H3K4me1, H3K4me3, and H3K36me3) and repressed (H3K27me3 and H3K9me3) chromatin states.
Here’s what they found:
- ATRTs display global depletion of H3K27ac
without a loss of other active marks and also show an unexpected global loss of
- Lentiviral rescue of SMARCB1 expression increases global levels of both marks in two ATRT cell lines
- Neuronal genes normally bound by SMARCB1 in healthy brain tissue are repressed by the H3K27me3 methylase EZH2 in ATRTs
- ATRTs are characterised by a large group genes (38% of promoters in the genome) that are active and occupied by EZH2 but surprisingly do no show H3K27me3 occupancy
- Though loss of SMARCB1 has previously been
shown to cause disassembly of SWI/SNF, the authors found residual SWI/SNF
occupancy maintains genes expression in the presence of the repressive Polycomb
complex in ATRTs
- Residual SWI/SNF is thus likely responsible for the transcriptional activity of these sites and not EZH2
EZH2 has been implicated in ATRTs before, but its targets have not been well defined. This study shows that residual SWI/SNF protects against polycomb-mediated repression by EZH2. This work also suggests that exploration of EZH2 as a target in these cancers will be a useful area for future research. Therapies targeting residual SWI/SNF complex components alone or in combination with EZH2 inhibition might be beneficial for treatment of ATRT patients. These new findings are nothing to be SNFed at and could be very useful for SWItching the way thinking about EZH2 in tumorigenesis.
SNF out the BAFling details of pediatric brain tumors in Cancer Cell, January 2019