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PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression [RNA-seq]

ABSTRACT: Genes encoding subunits of SWI/SNF(BAF) chromatin remodeling complexes are collectively mutated in nearly 25% of all cancers. Utilizing a genome-wide CRISPR-Cas9 screen, we identify PHF6 as a specific vulnerability in pediatric malignant rhabdoid tumors (RTs), which are driven by inactivation of the SMARCB1 subunit of SWI/SNF. We establish that PHF6 co-localizes with residual SWI/SNF subcomplexes at promoters and enhancers. Here, PHF6 facilitates transcriptional activation by regulating deposition of H3K14ac downstream of active promoters and contributes to the establishment of H3K27ac at active promoters and enhancers. We show that PHF6 is essential for the maintenance of these marks in part via the regulation of their writers, HB01 and CBP/p300, respectively. As it directly regulates the H3K14ac mark, PHF6 may regulate pausing and serve as a mediator between chromatin regulatory function and RNA POL II pause release. Together, our results establish a mechanistic basis for dependence upon PHF6 in SMARCB1-mutant RTs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180481 | GEO | 2024/06/07

REPOSITORIES: GEO

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PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression [ATAC-seq]

Project description:Genes encoding subunits of SWI/SNF(BAF) chromatin remodeling complexes are collectively mutated in nearly 25% of all cancers. Utilizing a genome-wide CRISPR-Cas9 screen, we identify PHF6 as a specific vulnerability in pediatric malignant rhabdoid tumors (RTs), which are driven by inactivation of the SMARCB1 subunit of SWI/SNF. We establish that PHF6 co-localizes with residual SWI/SNF subcomplexes at promoters and enhancers. Here, PHF6 facilitates transcriptional activation by regulating deposition of H3K14ac downstream of active promoters and contributes to the establishment of H3K27ac at active promoters and enhancers. We show that PHF6 is essential for the maintenance of these marks in part via the regulation of their writers, HB01 and CBP/p300, respectively. As it directly regulates the H3K14ac mark, PHF6 may regulate pausing and serve as a mediator between chromatin regulatory function and RNA POL II pause release. Together, our results establish a mechanistic basis for dependence upon PHF6 in SMARCB1-mutant RTs.

2024-06-07 | GSE180486 | GEO

PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression [ChIP-seq]

Project description:Genes encoding subunits of SWI/SNF chromatin remodeling complexes are mutated in nearly 25% of cancers. The SWI/SNF subunit SMARCB1 is the driving mutation in nearly all cases of rhabdoid tumor (RT), highly malignant cancers of childhood. While loss of SMARCB1 drives cancer, its absence also creates unique dependencies, which can illuminate mechanism and reveal potential therapeutic vulnerabilities. To identify such dependencies we undertook a genome-scale CRISPR screen comparing RT cell lines to 800 other cancer lines. We identified PHF6 as specifically essential for RT cell survival. Germline mutations in both SMARCB1 and PHF6 cause Coffin-Siris syndrome, and somatic mutations in PHF6 or SWI/SNF occur in T-ALL, suggesting a mechanistic link. We establish that PHF6 co-localizes with residual SWI/SNF complexes at active promoters and enhancers. We find that PHF6 is specifically required for H3K14ac accumulation immediately downstream of active promoters and for release of paused Pol II. Collectively, our work identifies novel integrated roles for PHF6 in chromatin and Pol II regulation, establishes a mechanistic basis for dependence upon PHF6 in RT, and reveals a novel potential therapeutic vulnerability in RT.

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PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression[CUT&RUN]

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SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [primary tissue_ChIP-seq]

Project description:SMARCB1 (SNF5/INI1/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 indistinguishable mutational landscapes, human RTs show distinct enhancer H3K27ac signatures, which reveal 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 across all subtypes, such as SPRY1, and other lineage-specific super-enhancers like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.

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SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [primary tissue_RNA-seq]

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SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [cell line_ChIP-seq]

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BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [RNA-seq]

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BRD9 defines a novel SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors [ChIP-seq]

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