ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice [primary cells_ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE71512 | GEO | 2016/11/21
SECONDARY ACCESSION(S): PRJNA291421
REPOSITORIES: GEO
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Project description:Genes encoding subunits of SWI/SNF chromatin remodeling complexes are collectively mutated in ~20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here, we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/beta-catenin, crucial gatekeepers in common forms of intestinal cancer. ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors (TFs) to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor suppressor function of ARID1A.
2016-11-21 | GSE71510 | GEO
Project description:Genes encoding subunits of SWI/SNF chromatin remodeling complexes are collectively mutated in ~20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here, we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/beta-catenin, crucial gatekeepers in common forms of intestinal cancer. ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors (TFs) to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor suppressor function of ARID1A.
2016-11-21 | GSE71513 | GEO
Project description:Genes encoding subunits of SWI/SNF chromatin remodeling complexes are collectively mutated in ~20% of all human cancers. Although ARID1A is the most frequent target of mutations, the mechanism by which its inactivation promotes tumorigenesis is unclear. Here, we demonstrate that Arid1a functions as a tumor suppressor in the mouse colon, but not the small intestine, and that invasive ARID1A-deficient adenocarcinomas resemble human colorectal cancer (CRC). These tumors lack deregulation of APC/beta-catenin, crucial gatekeepers in common forms of intestinal cancer. ARID1A normally targets SWI/SNF complexes to enhancers, where they function in coordination with transcription factors (TFs) to facilitate gene activation. ARID1B preserves SWI/SNF function in ARID1A-deficient cells, but defects in SWI/SNF targeting and control of enhancer activity cause extensive dysregulation of gene expression. These findings represent an advance in colon cancer modeling and implicate enhancer-mediated gene regulation as a principal tumor suppressor function of ARID1A.
2016-11-21 | GSE71511 | GEO
Project description:Every known SWI/SNF chromatin-remodeling complex incorporates an ARID DNA binding domain-containing subunit. Despite being a ubiquitous component of these complexes, physiological roles for this domain remain undefined. We screened an N-ethyl-N-nitrosurea (ENU) mutagenized library for ARID domain point mutations and generated an Arid1a/Baf250a hypomorphic allele. The mutant ARID1a (V1068G) protein is stably expressed at wild-type levels, and it is capable of assembling into a SWI/SNF complex with in vitro mononucleosome disruption activity. However, its capacity to bind DNA is lost. Consistent with defective DNA binding, mutant protein occupancy at known SWI/SNF target genes is decreased. Loss of DNA binding is associated with concurrent changes in SWI/SNF target gene expression. Mutant embryos manifest heart defects, fail to establish proper yolk sac vasculature, and exhibit hemorrhaging. As a result of these phenotypes, mutant embryos fail to establish proper circulation, culminating in ischemic arrest in utero between days 9.5 and 11.5. These data support a role for ARID1a-containing, BAF-A complexes in heart and extraembryonic vascular development, and indicate the ARID domain of ARID1a is essential in this regard. Hence, intrinsic ARID subunit-DNA interactions are required for normal SWI/SNF function in vivo. Four-condition experiment, wild-type vs Baf250a/Arid1a^V1068G/V1068G yolk sacs isolated at E8.5 and E9.5. Biological replicates: 3 per condition.
2012-01-15 | E-GEOD-32116 | biostudies-arrayexpress
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:Arid1a is the subunit of SWI/SNF complex, which was reported to guide SWI/SNF to DNA. Here, we found that loss of Arid1a in the liver and other adult tissues results in improved organ regeneration. Within SWI/SNF complexes, Arid1a physically interacts with C/ebpα, a hepatocyte transcription factor that drives maturation and limits proliferation. Genome-wide analysis showed that loss of Arid1a reduces the recruitment and activity of C/ebpα on target promoters, resulting in expression programs that favor regeneration and cellular fitness during injury. Arid1a binding is enriched in promoters near transcriptional start sites (TSSs), and C/ebpα binds at precisely the same positions, indicating that Arid1a facilitates C/ebpα binding across the genome. Perfuse and isolate primary hepatocytes from mice livers, analysis of genomic occupancy of C/ebpα and H3K4me2 in hepatocytes from Arid1a WT and Arid1a liver specific KO mice by ChIP-seq. Analysis of genomic occupancy of Arid1a in the hepatocytes from V5-Arid1a transgenic mouse by ChIP-seq.
2016-03-30 | E-GEOD-65167 | biostudies-arrayexpress
Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and is problematic because the tumor suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. Here, we report that the little-studied gene DDB1-CUL4 Associated Factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and promotes degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. Upon depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore SWI/SNF-mediated gene expression to levels sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality control factors may effectively reverse the malignant state of some cancers driven by disruption of tumor suppressor complexes.
2024-01-21 | PXD046273 | Pride
Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and is problematic because the tumor suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. Here, we report that the little-studied gene DDB1-CUL4 Associated Factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and promotes degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. Upon depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore SWI/SNF-mediated gene expression to levels sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality control factors may effectively reverse the malignant state of some cancers driven by disruption of tumor suppressor complexes.
2024-01-21 | PXD046276 | Pride
Project description:While oncogenes can potentially be inhibited with small molecules, the loss of tumor suppressors is more common and is problematic because the tumor suppressor proteins are no longer present to be targeted. Notable examples include SMARCB1-mutant cancers, which are highly lethal malignancies driven by the inactivation of a subunit of SWI/SNF chromatin remodeling complexes. To generate mechanistic insight into the consequences of SMARCB1 mutation and to identify vulnerabilities, we contributed 14 SMARCB1-mutant cell lines to a near genome-wide CRISPR screen as part of the Cancer Dependency Map Project1-3. Here, we report that the little-studied gene DDB1-CUL4 Associated Factor 5 (DCAF5) is required for the survival of SMARCB1-mutant cancers. We show that DCAF5 serves a quality control function for SWI/SNF complexes and promotes degradation of incompletely assembled SWI/SNF complexes in the absence of SMARCB1. Upon depletion of DCAF5, SMARCB1-deficient SWI/SNF complexes re-accumulate, bind to target loci, and restore SWI/SNF-mediated gene expression to levels sufficient to reverse the cancer state, including in vivo. Consequently, cancer results not from the loss of SMARCB1 function per se but rather from DCAF5-mediated degradation of SWI/SNF complexes. These data indicate that therapeutic targeting of ubiquitin-mediated quality control factors may effectively reverse the malignant state of some cancers driven by disruption of tumor suppressor complexes.
2024-01-21 | PXD046275 | Pride
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