A SWI/SNF-dependent transcriptional repression mediated by POU2AF2/C11orf53 at enhancer.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): LTQ Orbitrap Elite
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: 
Lu Wang
LAB HEAD: Lu Wang
PROVIDER: PXD043238 | Pride | 2024-01-19
REPOSITORIES: Pride
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Project description:Recent studies have identified a previously uncharacterized protein C11orf53 (now named POU2AF2/OCA-T1), functions as a new co-activator of POU2F3, the master transcription factor which is critical for both normal and neoplastic tuft cell identity and viability. Here, we demonstrated that POU2AF2 functions as an “Yin-Yang” factor which mediates both transcriptional activation and repression at distal enhance elements. Loss of POU2AF2 led to an inhibition of active enhancer nearby genes, such as tuft cell identity genes, and a derepression of Polycomb-dependent poised enhancer nearby genes, which are critical for cell viability and differentiation. Mechanistically, depletion of POU2AF2 leads to a global redistribution of the chromatin occupancy of SWI/SNF complex, resulting in a significant 3D genome structure change and a subsequent transcriptional reprogramming. Genome wide CRISPR screen further demonstrated that POU2AF2 depletion or SWI/SNF inhibition led to a PTEN-dependent cell growth defect, which revealed a potential role of POU2AF2-SWI/SNF axis in small cell lung cancer pathogenesis. Finally, pharmacological inhibition of SWI/SNF phenocopied POU2AF2 depletion in terms of gene expression alteration and cell viability decease in SCLC-P subtype cells. Therefore, impeding POU2AF2 mediated SWI/SNF function represents a potential therapeutic approach for human SCLC therapy.
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Project description:Notch signaling plays a key role in many cell fate decisions during development by directing different gene expression programs via the transcription factor CSL, known as Su(H) in Drosophila Which target genes are responsive to Notch signaling is influenced by the chromatin state of enhancers, yet how this is regulated is not fully known. Detecting a specific increase in the histone variant H3.3 in response to Notch signaling, we tested which chromatin remodelers or histone chaperones are required for the changes in enhancer accessibility to Su(H) binding. We show a crucial role for the Brahma SWI/SNF chromatin remodeling complex, including the actin-related BAP55 subunit, in conferring enhancer accessibility and enabling the transcriptional response to Notch activity. The Notch-responsive regions have high levels of nucleosome turnover which depend on the Brahma complex, increase in magnitude with Notch signaling, and primarily involve histone H3.3. Together these results highlight the importance of SWI/SNF-mediated nucleosome turnover in rendering enhancers responsive to Notch.
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Project description:SMARCB1 (also known as SNF5, INI1, and 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 having indistinguishable mutational landscapes, human rhabdoid tumors exhibit distinct enhancer H3K27ac signatures, which identify 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 by all subtypes, such as SPRY1, and other lineage-specific super-enhancers, such as SOX2 in brain-derived rhabdoid tumors. Taken together, our findings identify a new chromatin-based epigenetic mechanism underlying the tumor-suppressive activity of SMARCB1.
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Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cell types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 Mb downstream from Myc that are occupied by SWI/SNF as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in ?3% of acute myeloid leukemias. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs.
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Project description:Subunits of the SWI/SNF chromatin remodeling complex are frequently mutated in human cancers leading to epigenetic dependencies that are therapeutically targetable. The dependency on the polycomb repressive complex (PRC2) and EZH2 represents one such vulnerability in tumors with mutations in the SWI/SNF complex subunit, SNF5; however, whether this vulnerability extends to other SWI/SNF subunit mutations is not well understood. Here we show that a subset of cancers harboring mutations in the SWI/SNF ATPase, SMARCA4, is sensitive to EZH2 inhibition. EZH2 inhibition results in a heterogenous phenotypic response characterized by senescence and/or apoptosis in different models, and also leads to tumor growth inhibition in vivo. Lower expression of the SMARCA2 paralog was associated with cellular sensitivity to EZH2 inhibition in SMARCA4 mutant cancer models, independent of tissue derivation. SMARCA2 is suppressed by PRC2 in sensitive models, and induced SMARCA2 expression can compensate for SMARCA4 and antagonize PRC2 targets. The induction of SMARCA2 in response to EZH2 inhibition is required for apoptosis, but not for growth arrest, through a mechanism involving the derepression of the lysomal protease cathepsin B. Expression of SMARCA2 also delineates EZH2 inhibitor sensitivity for other SWI/SNF complex subunit mutant tumors, including SNF5 and ARID1A mutant cancers. Our data support monitoring SMARCA2 expression as a predictive biomarker for EZH2-targeted therapies in the context of SWI/SNF mutant cancers.
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Project description:The SWI/SNF chromatin-remodeling complex, pivotal in transcriptional regulation, has emerged as a significant player in tumorigenesis, unveiling therapeutic targeting prospects in specific malignancies. This investigation accentuates the potential of targeting the SWI/SNF complex in POU2F3-driven Small Cell Lung Cancer (SCLC) and POU2AF1-dependent multiple myelomas. Employing functional CRISPR screening and pharmacological validation, we identified a distinct and biased dependency of POU2F3-driven SCLC cells on the SWI/SNF complex. In vivo studies exhibited significant tumor growth inhibition in POU2F3-driven SCLC xenografts with an orally administered SMARCA2/4 PROTAC degrader. Furthermore, the exploration extended to POU2AF1 complex-dependent B-cell malignancies, revealing similar sensitivity to the SWI/SNF ATPase PROTAC degrader, suggesting a shared therapeutic potential in POU2F complex-driven malignancies. These collective findings highlight the SWI/SNF complex as a promising therapeutic target, catalyzing the advancement of innovative and efficacious treatment approaches to address these transcription factor-driven malignancies, addressing a critical medical challenge.
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Project description:The SWI/SNF chromatin-remodeling complex, pivotal in transcriptional regulation, has emerged as a significant player in tumorigenesis, unveiling therapeutic targeting prospects in specific malignancies. This investigation accentuates the potential of targeting the SWI/SNF complex in POU2F3-driven Small Cell Lung Cancer (SCLC) and POU2AF1-dependent multiple myelomas. Employing functional CRISPR screening and pharmacological validation, we identified a distinct and biased dependency of POU2F3-driven SCLC cells on the SWI/SNF complex. In vivo studies exhibited significant tumor growth inhibition in POU2F3-driven SCLC xenografts with an orally administered SMARCA2/4 PROTAC degrader. Furthermore, the exploration extended to POU2AF1 complex-dependent B-cell malignancies, revealing similar sensitivity to the SWI/SNF ATPase PROTAC degrader, suggesting a shared therapeutic potential in POU2F complex-driven malignancies. These collective findings highlight the SWI/SNF complex as a promising therapeutic target, catalyzing the advancement of innovative and efficacious treatment approaches to address these transcription factor-driven malignancies, addressing a critical medical challenge.
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