Mutations in the SWI/SNF chromatin remodeling complex induce metabolic rewiring and dependence on oxidative phosphorylation
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ABSTRACT:
PROVIDER: PRJNA429431 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5259560_1.fastq.gz | Fastqsanger.gz | |||
| SRR5259560_2.fastq.gz | Fastqsanger.gz | |||
| SRR5259561_1.fastq.gz | Fastqsanger.gz | |||
| SRR5259561_2.fastq.gz | Fastqsanger.gz | |||
| SRR5259562_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Mutations in the SWI/SNF chromatin remodeling complex induce metabolic rewiring and dependence on oxidative phosphorylation
| PRJNA429453 | ENA
Project description:Mutations in the SWI/SNF chromatin remodeling complex induce metabolic rewiring and dependence on oxidative phosphorylation [Affymetrix]
| PRJNA429526 | ENA
Project description:Lung cancer is a devastating disease that remains the top cause of cancer mortality. While targeted therapies against EGFR and EML4-ALK fusion and recent advances in immunotherapy have shown substantial clinical benefit for some patients, the vast majority of patients with lung cancer still lack effective therapies underscoring the dire need for more context-specific therapeutics. Cancer genomic studies have identified frequent genetic alterations in chromatin and epigenetic regulators including inactivating mutations in components of the SWI/SNF chromatin remodeling complex. In lung adenocarcinoma, about 20% of tumors have inactivating mutations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. With the aim of understanding the mechanism of tumor development driven by mutations in this complex, we developed a genetically engineered mouse (GEM) model of lung adenocarcinoma by selectively ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Cross species integrative gene expression analyses revealed signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant murine as well as human lung adenocarcinomas. We further show that SMARCA4 mutant cells have increased oxygen consumption and increased respiratory capacity primarily driven by increased expression of the mitochondrial master regulator, PGC1-α. Importantly, we show that SMARCA4 and other SWI/SNF mutant lung cancer cell lines and xenograft tumors have exquisite sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4 deficient cells have a blunted transcriptional response to energy stress creating a therapeutically attractive collateral vulnerability. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.
2018-06-17 | GSE109020 | GEO
Project description:Lung cancer is a devastating disease that remains the top cause of cancer mortality. While targeted therapies against EGFR and EML4-ALK fusion and recent advances in immunotherapy have shown substantial clinical benefit for some patients, the vast majority of patients with lung cancer still lack effective therapies underscoring the dire need for more context-specific therapeutics. Cancer genomic studies have identified frequent genetic alterations in chromatin and epigenetic regulators including inactivating mutations in components of the SWI/SNF chromatin remodeling complex. In lung adenocarcinoma, about 20% of tumors have inactivating mutations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. With the aim of understanding the mechanism of tumor development driven by mutations in this complex, we developed a genetically engineered mouse (GEM) model of lung adenocarcinoma by selectively ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Cross species integrative gene expression analyses revealed signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant murine as well as human lung adenocarcinomas. We further show that SMARCA4 mutant cells have increased oxygen consumption and increased respiratory capacity primarily driven by increased expression of the mitochondrial master regulator, PGC1-α. Importantly, we show that SMARCA4 and other SWI/SNF mutant lung cancer cell lines and xenograft tumors have exquisite sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4 deficient cells have a blunted transcriptional response to energy stress creating a therapeutically attractive collateral vulnerability. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.
2018-06-17 | GSE109010 | GEO
Project description:The current studies show that JMJD1A is phosphorylated at S265 by protein kinase A (PKA), and this is pivotal to activate expression of the b1-adrenergic receptor gene (Adrb1) and downstream targets including Ucp1. Phosphorylation of JMJD1A increases its interaction with the SWI/SNF nucleosome remodeling complex and DNA-bound PPARg. This complex conferred b-adrenergic-induced JMJD1A recruitment to target sites throughout the genome. Phospho-JMJD1A also facilitated long-range chromatin looping to recruit PPARg-bound distal-enhancers, SWI/SNF, and RNA polymerase close to the Adrb1 locus to activate transcription. Mutation of the PKA-phosphorylation site on JMJD1A abolished interactions with SWI/SNF without affecting demethylase activity suggesting the two functions are independent of each other. Our results show that JMJD1A demethylase is also a signal-sensing scaffold that regulates cAMP-responsive transcription via interactions with SWI/SNF and hormone stimulated higher-order chromatin conformational changes. There are 3 samples analyzed. No duplication from each sample. Isoproterenol stimulation at 0hr is used as the relative to fold change in manuscript.
2015-04-15 | E-GEOD-58936 | biostudies-arrayexpress
Project description:Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, ARID1A is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that ARID1A mutation creates a dependence on glutamine metabolism. SWI/SNF represses glutaminase I (GLS1) and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of ARID1A mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents a novel therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as ARID1A mutations.
2020-10-21 | MSV000086347 | MassIVE
Project description:Alterations in components of the SWI/SNF chromatin-remodeling complex occur in ~20% of all human cancers. For example, ARID1A is mutated in up to 62% of clear cell ovarian carcinoma (OCCC), a disease currently lacking effective therapies. Here we show that ARID1A mutation creates a dependence on glutamine metabolism. SWI/SNF represses glutaminase I (GLS1) and ARID1A inactivation upregulates GLS1. ARID1A inactivation increases glutamine utilization and metabolism through the tricarboxylic acid cycle to support aspartate synthesis. Indeed, glutaminase inhibitor CB-839 suppresses the growth of ARID1A mutant, but not wildtype, OCCCs in both orthotopic and patient-derived xenografts. In addition, glutaminase inhibitor CB-839 synergizes with immune checkpoint blockade anti-PDL1 antibody in a genetic OCCC mouse model driven by conditional Arid1a inactivation. Our data indicate that pharmacological inhibition of glutaminase alone or in combination with immune checkpoint blockade represents a novel therapeutic strategy for cancers involving alterations in the SWI/SNF complex such as ARID1A mutations.
2020-10-21 | MSV000086347 | GNPS
Project description:Tissue-specific transcription factors initiate differentiation toward a specialized cell type by inducing transcription-permissive chromatin modifications at target gene promoters, through the recruitment of the SWI/SNF chromatin-remodeling complex (1, 2). The molecular mechanism that regulates the chromatin re-distribution of SWI/SNF in response to differentiation signals is currently unknown. Here we show that the muscle determination factor MyoD and the SWI/SNF structural sub-unit, BAF60c (SMARCD3), form a complex on the regulatory elements of MyoD-target genes in undifferentiated myoblasts, prior to the activation of gene expression. MyoD-BAF60c complex is devoid of the ATP-dependent enzymatic sub-units Brg1 and Brm, is required for stable MyoD binding to Ebox sequences, and marks the chromatin for signal-dependent recruitment of the SWI/SNF core complex to muscle loci. BAF60c phosphorylation on a conserved threonine by differentiation-activated p38 signalling promotes the incorporation of MyoD-BAF60c into a Brg1-based SWI/SNF complex, which is competent to remodel the chromatin and activates transcription of MyoD-target genes. Our data support an unprecedented two-step model, by which pre-assembled BAF60c-MyoD complex directs the SWI/SNF complex chromatin re-distribution to muscle loci in response to differentiation cues. Differentiation of C2C12 cells individually interfered for BRG1, BAF60B, BAF60C
2011-03-07 | E-GEOD-24573 | 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