Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A SWI/SNF-dependent transcriptional regulation mediated by POU2AF2/C11orf53 at enhancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235704 | GEO | 2024/01/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Targeting the SWI/SNF complexes in POU2F transcription factor driven malignancies [RNA-seq]

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.

2024-02-15 | GSE247949 | GEO

Targeting the SWI/SNF complexes in POU2F transcription factor driven malignancies [ChIP-seq]

2024-02-15 | GSE247948 | GEO

Targeting the SWI/SNF complexes in POU2F transcription factor driven malignancies [ATAC-seq]

2024-02-15 | GSE247947 | GEO

Brd7, a novel PBAF-specific SWI/SNF subunit, is required for gene activation and repression in embryonic stem cells

Project description:The composition of chromatin remodeling complexes dictates how these enzymes control transcriptional programs and cellular identity. Here, we investigate the composition of SWI/SNF complexes in embryonic stem cells (ESCs). In contrast to differentiated cells, ESCs have a biased incorporation of certain paralogous SWI/SNF subunits, with low levels of Brm, BAF170 and ARID1B. Upon differentiation, the expression of these subunits increases, resulting in a higher diversity of compositionally distinct SWI/SNF enzymes. We also identify Brd7 as a novel component of the PBAF complex in both ESCs and differentiated cells. Using shRNA-mediated depletion of Brg1, we show that SWI/SNF can function as both a repressor and an activator in pluripotent cells, regulating expression of developmental modifiers and signaling components such as Nodal, ADAMTS1, Bmi-1, CRABP1 and TRH. Knock-down studies of PBAF-specific Brd7 and of a signature subunit within the BAF complex, ARID1A, show that these two sub-complexes affect SWI/SNF target genes differentially, in some cases even antagonistically. This may be due to their different biochemical properties. Finally, we examine the role of SWI/SNF in regulating its target genes during differentiation. We find that SWI/SNF affects recruitment of components of the pre-initiation complex in a promoter-specific manner, to modulate transcription positively or negatively. Taken together, our results provide insight into the function of compositionally diverse SWI/SNF enzymes that underlie their inherent gene-specific mode of action. R1 ESCs were infected in duplicates with shRNA targeting Brg1 or GLUT4 (as a control). Knockdown of Brg1 mRNA affected Brg1 protein levels efficiently. RNA was isolated 67 hours post-infection and analyzed using microarrays.

2010-03-04 | E-GEOD-7791 | biostudies-arrayexpress

Transcription profiling of fission yeast strains identifies widespread requirement for SWI/SNF and RSC on transcription

Project description:SWI/SNF chromatin remodeling complexes play critical roles in transcription and other chromatin-related processes. The analysis of the two members of this class in Saccharomyces cerevisiae, SWI/SNF and RSC, has heavily contributed to our understanding of these complexes. To understand the in vivo functions of SWI/SNF and RSC in an evolutionarily distant organism, we have characterized these complexes in Schizosaccharomyces pombe. While core components are conserved between the two yeasts, the compositions of S. pombe SWI/SNF and RSC differ from their S. cerevisiae counterparts and in some ways are more similar to metazoan complexes. Furthermore, several of the conserved proteins, including actin-like proteins, are strikingly different between the two yeasts with respect to their requirement for viability. Finally, phenotypic and microarray analyses identified widespread requirements for SWI/SNF and RSC on transcription including strong evidence that SWI/SNF directly represses iron transport genes.

2008-06-13 | E-MTAB-31 | biostudies-arrayexpress

POU2AF2/C11orf53 functions as a co-activator of POU2F3 by maintaining chromatin accessibility and enhancer activity

Project description:Small cell lung cancer (SCLC), accounting for around 15% of all lung cancers, often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. The POU class 2 homeobox 3 (POU2F3) is a master regulator of tuft cell identity and defines a subtype of SCLC tumors (SCLC-P subtype) that lack the expression of neuroendocrine markers. Here, we have identified a previously uncharacterized protein C11orf53, which is co-expressed with POU2F3 in both SCLC cell lines and patient samples, and defines the same SCLC subtype. C11orf53 is an essential gene for SCLC-P subtype cells’ survival based on genome wide CRISPR screen, and genetic depletion of C11orf53 or POU2F3 induces apoptosis in different SCLC-P subtype cell lines. Furthermore, our biochemical and genome-wide studies have demonstrated that C11orf53 is a novel chromatin-bound protein that occupies broad active enhancer domains and regulates gene expression at active enhancers. Mechanistically, C11orf53 directly interacts with POU2F3 at the POUs domain, and is recruited to chromatin by POU2F3. Depletion of C11orf53 dramatically reduced enhancer H3K27ac levels and chromatin accessibility, resulting a reduction of the expression of POU2F3-dependent tuft cell markers. Based on the expression pattern and molecular function, we have renamed C11orf53 as "POU Class 2 Homeobox Associating Factor 2" (POU2AF2). In summary, our study has identified a new co-activator of POU2 family transcription factors, and sheds light on the therapeutic potential of targeting POU2AF2/POU2F3 heterodimer in human SCLC.

2022-09-28 | GSE197426 | GEO

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Project description:Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance seen in 10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify SWI/SNF subunits that are deregulated in NEPC, demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease and that SMARCA4 depletion impairs prostate cancer cell growth. We also show that SWI/SNF complexes interact with different lineage-specific factors in prostate adenocarcinoma and in NEPC cells, and that induction of lineage plasticity through depletion of REST is accompanied by changes in SWI/SNF genome occupancy. These data suggest a specific role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

2020-11-04 | PXD016861 | Pride

Androgen receptor-negative prostate cancer is vulnerable to SWI/SNF-targeting degrader molecules

Project description:The switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex becomes frequently deregulated in advanced castration-resistant prostate cancer (CRPC). SWI/SNF ATPase degrader molecules, also known as Proteolysis targeting chimera (PROTAC), offer a novel approach to tackle resistance to androgen receptor (AR) antagonists in AR-dependent CRPC (CRPC-AR). However, the frequent emergence of AR-negative CRPC remains a major clinical hurdle. We investigated SWI/SNF ATPase targeting agents in AR-negative CRPC. SWI/SNF targeting PROTAC treatment reduced the viability of both CRPC-AR and WNT-signaling dependent CRPC (CRPC-WNT), which accounts for about 10% of all clinical CRPC cases. In CRPC-WNT, we characterized that SWI/SNF ATPase SMARCA4 depletion interfered with WNT signaling via the master transcriptional regulator TCF7L2 (TCF4). Functionally, TCF7L2 maintains proliferation via the AP-1/MAPK signaling axis in this subtype of CRPC.

2024-03-18 | GSE261446 | GEO

Differential gene expression in paired SMC vs. Non-SMC

Project description:Poor prognosis of small cell lung cancer (SCLC) is mainly attributed to its highly metastatic capability. Here we identify the SMC and Non-SMC from Rb1L/L/Trp53 L/L mouse model through FACS with NE and mensenchymal markers. In order to identify functions of these two subpopulations during SCLC malignant progression, we compared their metastatic capability by allograft experiment. In addition, we find that the SMC is progressively transited from the Non-SCLC during mouse SCLC malignant progression. Further investigation reveals that genetic disruption of the SWI/SNF chromatin-remodeling complex, in RP model abrogates SMC phenotype maintenance and SCLC metastasis. In search of important downstream regulators, we find that TAZ, the core transcription cofactor of the Hippo pathway, is epigenetically silenced by SWI/SNF complex during this process. Collectively, our data link phenotypic transition to cancer metastasis and identify TAZ as a critical molecular switch that controls SCLC plasticity.

2022-08-24 | GSE158293 | GEO

Differential gene expression in SMC Ctrl vs TAZ4SA

2022-08-24 | GSE158290 | GEO