RESUMO
The mechanism controlling the dynamic targeting of SWI/SNF has long been postulated to be coordinated by transcription factors (TFs), yet demonstrating a specific TF influence has proven difficult. Here we take a multi-omics approach to interrogate transient SWI/SNF interactors, chromatin targeting and the resulting three-dimensional epigenetic landscape. We utilize the labeling technique TurboID to map the SWI/SNF interactome and identify the activator protein-1 (AP-1) family members as critical interacting partners for SWI/SNF complexes. CUT&RUN profiling demonstrates SWI/SNF targeting enrichment at AP-1 bound loci, as well as SWI/SNF-AP-1 cooperation in chromatin targeting. HiChIP reveals AP-1-SWI/SNF-dependent restructuring of the three-dimensional promoter-enhancer architecture and generation of enhancer hubs. Through interrogation of the SWI/SNF-AP-1 interaction, we demonstrate an SWI/SNF dependency on AP-1-mediated chromatin localization. We propose that pioneer factors, such as AP-1, bind and target SWI/SNF to inactive chromatin, where it restructures the genomic landscape into an active state through epigenetic rewiring spanning multiple dimensions.
Assuntos
Cromatina , Fator de Transcrição AP-1 , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Montagem e Desmontagem da Cromatina , Proteínas Nucleares/metabolismo , Regiões Promotoras GenéticasRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Bromodomain-containing protein 9 (BRD9) is a recently identified subunit of SWI/SNF(BAF) chromatin remodeling complexes, yet its function is poorly understood. Here, using a genome-wide CRISPR-Cas9 screen, we show that BRD9 is a specific vulnerability in pediatric malignant rhabdoid tumors (RTs), which are driven by inactivation of the SMARCB1 subunit of SWI/SNF. We find that BRD9 exists in a unique SWI/SNF sub-complex that lacks SMARCB1, which has been considered a core subunit. While SMARCB1-containing SWI/SNF complexes are bound preferentially at enhancers, we show that BRD9-containing complexes exist at both promoters and enhancers. Mechanistically, we show that SMARCB1 loss causes increased BRD9 incorporation into SWI/SNF thus providing insight into BRD9 vulnerability in RTs. Underlying the dependency, while its bromodomain is dispensable, the DUF3512 domain of BRD9 is essential for SWI/SNF integrity in the absence of SMARCB1. Collectively, our results reveal a BRD9-containing SWI/SNF subcomplex is required for the survival of SMARCB1-mutant RTs.
