The SWI/SNF complex regulates the expression of miR-222, a tumor suppressor microRNA in lung adenocarcinoma
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ABSTRACT:
PROVIDER: PRJNA703362 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13754964.fastq.gz | Fastqsanger.gz | |||
| SRR13754965.fastq.gz | Fastqsanger.gz | |||
| SRR13754966.fastq.gz | Fastqsanger.gz | |||
| SRR13754967.fastq.gz | Fastqsanger.gz | |||
| SRR13754968.fastq.gz | Fastqsanger.gz |
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Project description:Mammalian SWI/SNF complexes are considered as key epigenetic regulators and they are recurrently mutated in many types of cancer. Most of the studies of these chromatin remodeling complexes are focused on their role in regulating protein-coding genes. However, here we show that the SWI/SNF complex is able to control the expression of microRNAs. We used a SMARCA4-deficient model of lung adenocarcinoma where we could track changes of the miRNome upon SMARCA4 restoration. We found that exogenous SMARCA4 was successfully incorporated into endogenous SWI/SNF complexes and that these SMARCA4-SWI/SNF complexes induced significant changes in the expression of cancer-related microRNAs. The most significantly dysregulated miRNA was miR-222, whose expression was promoted by SMARCA4-SWI/SNF complexes but not by SMARCA2-SWI/SNF complexes via their direct binding to a miR-222 enhancer region. Importantly, miR-222 expression decreased cell viability and impaired cell clonogenicity, phenocopying the tumor-suppressor role of the SMARCA4-SWI/SNF complex in lung cancer. Finally, we showed that the miR-222 enhancer does not interact with any cancer-related protein-coding genes, supporting that its tumor suppressor effect may be exerted via miR-222. Overall, this study highlights the relevant role of the SWI/SNF complex in regulating the expression of the non-coding genome.
2021-07-20 | GSE167140 | GEO
Project description:Mammalian SWI/SNF complexes are ATP-dependent chromatin remodelers composed of varying combinations of subunits that, together, fine-tune transcriptional regulation and genome integrity. SWI/SNF complex subunits have been identified as major targets of mutations in several tumor types suggesting a relevant role in tumorigenesis. However, there is a lack of comprehensive studies of the whole SWI/SNF complex in lung adenocarcinoma (LUAD). Here, we combined genomic, transcriptomic, and proteomic approaches to identify which SWI/SNF subunits are present in lung cells, as well as their mutational status, mRNA levels, and protein levels in LUAD. For these purposes, we combined data from LUAD primary tumors, normal lung and LUAD cell lines, and external LUAD data from The Cancer Genome Atlas. Importantly, we found that mutations in the SWI/SNF complex in LUAD not only present a high incidence but we also observed that only the mutational status of the SWI/SNF complex and not the mutations in any of the top ten LUAD driver genes is associated with poorer overall survival in LUAD patients. Furthermore, we showed that the expression of the SWI/SNF complex in LUAD suffers an overall repression that cannot be explained exclusively by genetic alterations. Based on our findings, we propose that SWI/SNF-mutant LUAD tumors should be considered as a distinct subgroup with practical applications in the prognosis and follow-up of LUAD patients.
2022-04-01 | PXD017397 | Pride
Project description:Precise nucleosome-positioning patterns at promoters are thought to be crucial for faithful transcriptional regulation. However, the mechanisms by which these patterns are established and dynamically maintained and subsequently contribute to transcriptional control are poorly understood. The Swi/Snf (Baf) chromatin remodeling complex is a master developmental regulator and tumor suppressor that is capable of mobilizing nucleosomes in biochemical assays. Yet, its role in establishing the nucleosome landscape in vivo is unclear. Here we have inactivated Snf5 and Brg1, core subunits of the mammalian Swi/Snf complex, to evaluate their effects on chromatin structure and transcription levels genome-wide. We find that inactivation of either subunit leads to disruptions of specific nucleosome patterning combined with a loss of overall nucleosome occupancy at a large number of promoters, regardless of their association with CpG islands. These rearrangements are accompanied by gene expression changes that promote cell proliferation. Collectively, these findings define a direct relationship between chromatin-remodeling complexes, chromatin structure, and transcriptional regulation. Gene expression was measured in three cell types using multiple replicates for each sample.
2013-06-04 | E-GEOD-46645 | biostudies-arrayexpress
Project description:Precise nucleosome-positioning patterns at promoters are thought to be crucial for faithful transcriptional regulation. However, the mechanisms by which these patterns are established and dynamically maintained and subsequently contribute to transcriptional control are poorly understood. The Swi/Snf (Baf) chromatin remodeling complex is a master developmental regulator and tumor suppressor that is capable of mobilizing nucleosomes in biochemical assays. Yet, its role in establishing the nucleosome landscape in vivo is unclear. Here we have inactivated Snf5 and Brg1, core subunits of the mammalian Swi/Snf complex, to evaluate their effects on chromatin structure and transcription levels genome-wide. We find that inactivation of either subunit leads to disruptions of specific nucleosome patterning combined with a loss of overall nucleosome occupancy at a large number of promoters, regardless of their association with CpG islands. These rearrangements are accompanied by gene expression changes that promote cell proliferation. Collectively, these findings define a direct relationship between chromatin-remodeling complexes, chromatin structure, and transcriptional regulation. Profiling Brg1 binding in murine embryonic fibroblasts
2013-06-04 | E-GEOD-46587 | biostudies-arrayexpress
Project description:Precise nucleosome-positioning patterns at promoters are thought to be crucial for faithful transcriptional regulation. However, the mechanisms by which these patterns are established and dynamically maintained and subsequently contribute to transcriptional control are poorly understood. The Swi/Snf (Baf) chromatin remodeling complex is a master developmental regulator and tumor suppressor that is capable of mobilizing nucleosomes in biochemical assays. Yet, its role in establishing the nucleosome landscape in vivo is unclear. Here we have inactivated Snf5 and Brg1, core subunits of the mammalian Swi/Snf complex, to evaluate their effects on chromatin structure and transcription levels genome-wide. We find that inactivation of either subunit leads to disruptions of specific nucleosome patterning combined with a loss of overall nucleosome occupancy at a large number of promoters, regardless of their association with CpG islands. These rearrangements are accompanied by gene expression changes that promote cell proliferation. Collectively, these findings define a direct relationship between chromatin-remodeling complexes, chromatin structure, and transcriptional regulation. Nucleosome profiling in three cell types
2013-06-04 | E-GEOD-38670 | biostudies-arrayexpress
Project description:Precise nucleosome-positioning patterns at promoters are thought to be crucial for faithful transcriptional regulation. However, the mechanisms by which these patterns are established and dynamically maintained and subsequently contribute to transcriptional control are poorly understood. The Swi/Snf (Baf) chromatin remodeling complex is a master developmental regulator and tumor suppressor that is capable of mobilizing nucleosomes in biochemical assays. Yet, its role in establishing the nucleosome landscape in vivo is unclear. Here we have inactivated Snf5 and Brg1, core subunits of the mammalian Swi/Snf complex, to evaluate their effects on chromatin structure and transcription levels genome-wide. We find that inactivation of either subunit leads to disruptions of specific nucleosome patterning combined with a loss of overall nucleosome occupancy at a large number of promoters, regardless of their association with CpG islands. These rearrangements are accompanied by gene expression changes that promote cell proliferation. Collectively, these findings define a direct relationship between chromatin-remodeling complexes, chromatin structure, and transcriptional regulation. Nucleosome profiling in three different cell types under two digestion conditions
2013-06-04 | E-GEOD-46586 | biostudies-arrayexpress
Project description:Here we performed transcriptional profiling of the prostate cancer cell lines LNCaP and 22Rv1 comparing non-targeting siRNA treatment versus siRNAs targeting SWI/SNF complex proteins (SMARCA2, SMARCA4, and SMARCB1). Goal was to determine the effect of SWI/SNF knockdown on gene expression in prostate cancer. Two-condition experiment: non-targeting siRNA versus SWI/SNF-siRNA treated cells. Three SWI/SNF proteins were targeted: SMARCA2, SMARCA4, and SMARB1. Biological replicates: 1 control replicate, 2 treatment replicates per SWI/SNF protein. Technical replicates: 1 replicate per SWI/SNF protein. Cell lines: 22Rv1 and LNCaP.
2013-07-20 | E-GEOD-40384 | biostudies-arrayexpress
Project description:A systems understanding of nuclear organization and events is critical for determining how cells divide, differentiate and respond to stimuli and for identifying the causes of diseases. Chromatin remodeling complexes such as SWI/SNF have been implicated in a wide variety of cellular processes including gene expression, nuclear organization, centromere function and chromosomal stability, and mutations in SWI/SNF components have been linked to several types of cancer. To better understand the biological processes in which chromatin remodeling proteins participate we globally mapped binding regions for several components of the SWI/SNF complex throughout the human genome using ChIP-Seq. SWI/SNF components were found to lie near regulatory elements integral to transcription (e.g. 5M-bM-^@M-^Y ends, RNA Polymerases II and III and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins and DNA replication origins). To further elucidate the association of SWI/SNF subunits with each other as well as with other nuclear proteins we also analyzed SWI/SNF immunoprecipitated complexes by mass spectrometry. Individual SWI/SNF factors are associated with their own family members as well as with cellular constituents such as nuclear matrix proteins, key transcription factors and centromere components implying a ubiquitous role in gene regulation and nuclear function. We find an overrepresentation of both SWI/SNF-associated regions and proteins in cell cycle and chromosome organization. Taken together the results from our ChIP and immunoprecipitation experiments suggest that SWI/SNF facilitates gene regulation and genome function more broadly and through a greater diversity of interactions than previously appreciated. ChIP-Seq analysis of the SWI/SNF subunits Ini1, Brg1, BAF155 and BAF170 in HeLa S3 cells
2011-01-10 | E-GEOD-24397 | biostudies-arrayexpress
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
Project description:The SWI/SNF (or BAF) complex is an essential chromatin remodeler that regulates DNA accessibility at developmental genes and enhancers. SWI/SNF subunits are among the most frequently mutated genes in cancer and neurodevelopmental disorders. These mutations are often heterozygous loss-of-function alleles, indicating a dosage-sensitive role for SWI/SNF subunits in chromatin regulation. However, the molecular mechanisms that regulate SWI/SNF subunit dosage to ensure proper complex assembly remain largely unexplored. We performed a genome-wide CRISPR KO screen, using epigenome editing in mouse embryonic stem cells, and identified Mlf2 and Rbm15 as regulators of SWI/SNF complex activity. First, we show that MLF2, a poorly characterized chaperone protein, regulates a subset of SWI/SNF target genes by promoting its chromatin remodeling activity. Rapid degradation of MLF2 reduces chromatin accessibility at sites that depend on high levels of SWI/SNF binding to maintain open chromatin. Next, we find that RBM15, part of the m6A RNA methylation writer complex, controls m6A modifications on specific SWI/SNF mRNAs to regulate protein levels of these subunits. Misregulation of m6A methylation causes overexpression of core SWI/SNF subunits leading to the assembly of incomplete complexes lacking the catalytic ATPase/ARP subunits. These data indicate that targeting modulators of SWI/SNF complex assembly may offer a potent therapeutic strategy for diseases associated with impaired chromatin remodeling.
2025-04-28 | PXD061408 | Pride