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Inactivation of ARID1A-SWI/SNF Complex Alters Chromatin Compactness at Enhancer Regions and Affects Transcription of Key Tumor Signaling Circuitry [ATAC-Seq]

ABSTRACT: Somatic mutations in ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human malignancies linked to endometriosis. Through comprehensive chromatin immunoprecipitation sequencing and transposase-accessible chromatin sequencing, we identified chromatin binding regions for ARID1A/BRG1-containing SWI/SNF remodeling complexes, which were enriched at enhancers and corresponded to a euchromatin state. ARID1A deletion caused global affinity reduction of BRG1-containing complexes in chromatin. Integrative analyses with transcriptome data obtained from endometrial epithelium and human endometrioid carcinomas identified high-confidence ARID1A-regulated genes that participate in tissue regeneration and tumorigenesis. Deletion of Arid1a was found to inactivate the TGF-β pathway and to accelerate tumor progression from pre-cancerous lesions to endometrioid carcinomas. Collectively, this study establishes functional roles of ARID1A mutation and loss in tumor progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106658 | GEO | 2020/06/08

REPOSITORIES: GEO

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Inactivation of ARID1A-SWI/SNF Complex Alters Chromatin Compactness at Enhancer Regions and Affects Transcription of Key Tumor Signaling Circuitry [RNA-Seq]

Project description:Somatic mutations in ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human malignancies linked to endometriosis. Through comprehensive chromatin immunoprecipitation sequencing and transposase-accessible chromatin sequencing, we identified chromatin binding regions for ARID1A/BRG1-containing SWI/SNF remodeling complexes, which were enriched at enhancers and corresponded to a euchromatin state. ARID1A deletion caused global affinity reduction of BRG1-containing complexes in chromatin. Integrative analyses with transcriptome data obtained from endometrial epithelium and human endometrioid carcinomas identified high-confidence ARID1A-regulated genes that participate in tissue regeneration and tumorigenesis. Deletion of Arid1a was found to inactivate the TGF-β pathway and to accelerate tumor progression from pre-cancerous lesions to endometrioid carcinomas. Collectively, this study establishes functional roles of ARID1A mutation and loss in tumor progression.

2020-06-08 | GSE106661 | GEO

Inactivation of ARID1A-SWI/SNF Complex Alters Chromatin Compactness at Enhancer Regions and Affects Transcription of Key Tumor Signaling Circuitry [RNA-Seq, mouse]

2020-06-08 | GSE106662 | GEO

ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives HCC metastasis [RNA-seq]

Project description:ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including hepatocellular carcinoma (HCC). Previous studies have demonstrated that ARID1A deficiency can cause HCC metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms of which remain poorly understood. Whether and how SWI/SNF complex could function as an architectural cooperator to synergistically stabilize chromatin organization should be explored, particular in tumorigenesis. Here we reveal that SWI/SNF complex acts as a potential architectural cooperator via BRG1-RAD21 axis for chromatin organization maintenance; ARID1A deficiency weakens the interaction and thus loosens chromatin compactness, which drives HCC metastasis dependent on the conformational dysregulation on some key genes.

2020-08-24 | GSE152050 | GEO

ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives HCC metastasis [ChIP-seq]

2020-08-24 | GSE152049 | GEO

Protein-protein interactions of BRG1 or BRG1-HSA in SW13 cells

Project description:The SWI/SNF complex remodels chromatin in an ATP-dependent manner through the ATPase subunits BRG1 and BRM. Chromatin remodeling alters nucleosome structure to change gene expression, however aberrant remodeling and gene expression can result in cancer. The function and localization on chromatin of the SWI/SNF complex depends on the protein makeup of the complex. Here we report the protein-protein interactions of wild-type BRG1 or mutant BRG1 in which the HSA domain has been deleted (BRG1-HSA). We demonstrate the interaction of BRG1 with most SWI/SNF complex members and a failure of a number of these members to interact with BRG1-HSA. These results demonstrate that the HSA domain of BRG1 is a critical interaction platform for the correct formation of SWI/SNF remodeling complexes.

2023-02-15 | PXD029647 | Pride

Transcriptome analysis of Arid1a-deficient IPMN and Brg1-deficient IPMN

Project description:Mutations of subunit genes of the SWI/SNF chromatin remodeling complexes were found in 12-23% of human Pancreatic Ductal Adenocarcinoma (PDAC). We previously showed that Brg1, a catalytic ATPase subunit of the SWI/SNF chromatin remodeling complexes, inhibits the formation of intraductal pancreatic mucinous neoplasms (IPMN) and IPMN-derived PDAC from ductal cells. On the other hand, ARID1A is the most frequent target of mutations in the SWI/SNF chromatin remodeling complexes in human PDAC. We found that Arid1a loss in the context of mutant Kras resulted in formation of IPMN and PDAC. We also found that the incidence of PDAC formation in Ptf1a-Cre; KrasG12D; Arid1af/f mice was markedly lower than that in Ptf1a-Cre; KrasG12D; Brg1f/f mice despite the similarities between Arid1a-deficient and Brg1-deficient IPMNs. We extracted total RNA from intraductal papillary mucinous neoplasms (IPMNs) in Ptf1a-Cre; KrasG12D; Arid1af/f and Ptf1a-Cre; KrasG12D; Brg1f/f mice and perform microarray analysis.

2018-03-31 | GSE96926 | 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

ARID-DNA interactions are essential for SWI/SNF function

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

SWI/SNF inactivation in the endometrial epithelium leads to loss of epithelial integrity [Mouse EPCAM]

Project description:Although ARID1A mutations are a hallmark feature, mutations in other SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling subunits are also observed in endometrial neoplasms. Here, we interrogated the roles of Brahma/SWI2-related gene 1 (BRG1, SMARCA4), the SWI/SNF catalytic subunit, in the endometrial epithelium. BRG1 loss affects more than one-third of all active genes and highly overlaps with the ARID1A gene regulatory network. Chromatin immunoprecipitation studies revealed widespread subunit-specific differences in transcriptional regulation, as BRG1 promoter interactions are associated with gene activation, while ARID1A binding is associated with gene repression. However, we identified a physiologically relevant subset of BRG1 and ARID1A co-regulated epithelial identity genes. Mice were genetically engineered to inactivate BRG1 specifically in the endometrial epithelium. Endometrial glands were observed embedded in uterine myometrium, indicating adenomyosis-like phenotypes. Molecular similarities were observed between BRG1 and ARID1A mutant endometrial cells in vivo, including loss of epithelial cell adhesion and junction genes. Collectively, these studies illustrate overlapping contributions of multiple SWI/SNF subunit mutations in the translocation of endometrium to distal sites, with loss of cell integrity being a common feature in SWI/SNF mutant endometrial epithelia.

2020-10-20 | GSE152662 | GEO

SWI/SNF inactivation in the endometrial epithelium leads to loss of epithelial integrity [12Z RNA-seq]

2020-10-20 | GSE152661 | GEO

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