Dataset Information

BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors.

ABSTRACT: 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.

SUBMITTER: Wang X

PROVIDER: S-EPMC6479050 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors.

Wang Xiaofeng X Wang Su S Troisi Emma C EC Howard Thomas P TP Haswell Jeffrey R JR Wolf Bennett K BK Hawk William H WH Ramos Pilar P Oberlick Elaine M EM Tzvetkov Evgeni P EP Ross Aaron A Vazquez Francisca F Hahn William C WC Park Peter J PJ Roberts Charles W M CWM

Nature communications 20190423 1

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-c ...[more]

PMID: 31015438

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Project description:BackgroundRhabdoid tumors (RTs) arise within (atypical teratoid/rhabdoid tumor [AT/RT]) or outside the brain (extra [e]CNS-RT) and are driven mainly by inactivation of the SWItch/sucrose nonfermentable (SWI/SNF) complex subunit SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1). A pathognomonic hallmark of RTs is heterogeneous multilineage differentiation, including anomalous neuronal differentiation in some eCNS-RTs. Because remodeling of the SWI/SNF complex regulates differentiation, we hypothesized that SWI/SNF Brahma-associated factors (BAF) and polybromo-associated BAF (PBAF) complex heterogeneity are related to both multilineage differentiation and clinical outcome.MethodsWe performed an integrated analysis of SWI/SNF complex alterations in the developing kidney and cerebellum (most common regions of RT origin) in comparison to eCNS-RT (n = 14) and AT/RT (n = 25) tumors. RT samples were interrogated using immunohistochemistry, DNA methylation, and gene expression analyses.ResultsThe SWI/SNF BAF paralogs actin-like protein (ACTL)6A and ACTL6B were expressed in a mutually exclusive manner in the developing cerebellum and kidney. In contrast, a subset of eCNS-RTs lost mutual exclusivity and coexpressed both subunits. These tumors showed aberrant DNA methylation of genes that regulate neuronal and renal development and demonstrated immunohistochemical evidence of neuronal differentiation. In addition, low expression of the PBAF subunit polybromo-1 (PBRM1) identified a group of AT/RTs in younger children with better overall prognosis. PBRM1-low AT/RT and eCNS-RTs showed altered DNA methylation and gene expression in immune-related genes. PBRM1 knockdown resulted in lowering immunosuppressive cytokines, and PBRM1 levels in tumor samples showed an inverse relationship with cluster of differentiation (CD)8 cytotoxic T-cell infiltration.ConclusionsHeterogeneity in SWI/SNF BAF (ACTL6A/ACTL6B) and PBAF (PBRM1) subunits is related to histogenesis, contributes to the immune microenvironment and prognosis in RTs, and may inform opportunities to develop immunotherapies.

Dataset Information

BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors.

Publications

BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors.

Similar Datasets

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