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Deciphering the novel regulatory mechanisms and biological implications of ARID1A C-terminal missense mutations in cancer [RNA-seq]

ABSTRACT: ARID1A (the AT-rich interaction domain 1A, also known as BAF250a), a pivotal component of the SWI/SNF chromatin remodeling complex, is frequently mutated in various cancers. In this study, we discovered that mutations such as ARID1A V2084D or V2087E lead to the binding of ARID1A mutant with the nucleocytoplasmic shuttling protein XPO1, facilitating ARID1A mutant transport to the cytoplasm. Subsequently, the E3 ubiquitin ligase STUB1 recognizes and ubiquitinates ARID1A mutant protein, marking it for degradation. This reduction in protein levels due to the mutation impedes the assembly of the cBAF complex and the expression of tumor-suppressive target genes, ultimately contributing to a malignant phenotype. Knocked down STUB1 or inhibit XPO1 activity stabilizes the ARID1A mutant protein, retaining it in the nucleus, which restores the assembly of the cBAF complex, chromatin remodeling function, and the expression of critical genes, thereby decrease the tumor burden.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254867 | GEO | 2024/10/09

REPOSITORIES: GEO

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Deciphering the novel regulatory mechanisms and biological implications of ARID1A C-terminal missense mutations in cancer [ChIP-Seq]

Project description:ARID1A (the AT-rich interaction domain 1A, also known as BAF250a), a pivotal component of the SWI/SNF chromatin remodeling complex, is frequently mutated in various cancers. In this study, we discovered that mutations such as ARID1A V2084D or V2087E lead to the binding of ARID1A mutant with the nucleocytoplasmic shuttling protein XPO1, facilitating ARID1A mutant transport to the cytoplasm. Subsequently, the E3 ubiquitin ligase STUB1 recognizes and ubiquitinates ARID1A mutant protein, marking it for degradation. This reduction in protein levels due to the mutation impedes the assembly of the cBAF complex and the expression of tumor-suppressive target genes, ultimately contributing to a malignant phenotype. Knocked down STUB1 or inhibit XPO1 activity stabilizes the ARID1A mutant protein, retaining it in the nucleus, which restores the assembly of the cBAF complex, chromatin remodeling function, and the expression of critical genes, thereby decrease the tumor burden.

2024-10-09 | GSE254865 | GEO

Deciphering the novel regulatory mechanisms and biological implications of ARID1A C-terminal missense mutations in cancer [ATAC-Seq]

2024-10-09 | GSE254864 | GEO

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 localization during macrophage inflammatory response [ChIP-seq_SWISNF]

Project description:To understand how the SWI/SNF complex help establish appropriate epiegentic landscape during macrophage inflammatory response, we profiled the binding sites of BRG1 (all BAF), ARID1A (cBAF), BRD9 (ncBAF), and PHF10 (PBAF) for WT BMDMs with 0hr, 1hr, or 4hr LipidA stimulation. To assess the modes of action for cBAF inhibitor BRDK98, we also performed ARID1A ChIP for BRDK98-treated BDMDs after 0hr and 4hr of LipidA stimulation.

2024-06-05 | GSE242801 | GEO

Localized condensation of the cBAF remodeler is governed by ARID1A/B and is required for transcriptional activation [ATAC-seq]

Project description:This study investigates the role of the ARID1A/B subunits of the cBAF complex using in vitro and cell-based models. Specifically, we find that the N-terminal disordered region of ARID1A/B and the DNA binding ARID domain are required for condensation and proper orientation on chromatin respectively.

2023-10-01 | GSE209959 | GEO

Localized condensation of the cBAF remodeler is governed by ARID1A/B and is required for transcriptional activation [CUT&Tag]

2023-10-01 | GSE209955 | GEO

Localized condensation of the cBAF remodeler is governed by ARID1A/B and is required for transcriptional activation [RNA-seq]

2023-10-01 | GSE209953 | GEO

The Pkm duet: Coordinating C2C12 myoblast proliferation and differentiation through Histone 3 phosphorylation and cBAF complex dynamics

Project description:Pkm1 and Pkm2 kinases are expressed in differentiating skeletal myoblasts. Knockdown of Pkm1 or Pkm2, therefore, can affect myoblast differentiation, by two independent regulatory mechanisms involving histone phosphorylation and chromatin remodeling complexes. Pkm2 KD in C2C12 cells reduced the chromatin marks of phosphorylated H3-T6, H3-T11 and H3-T45 into several essential myogenic promoters, and consequently, prevented their expression. Also, the transcriptional analysis demonstrated that Pkm2 is required for the expression of the cBAF-specific subunits Dpf2 and Baf250a, which we have previously demonstrated are essential for myogenesis. In contrast, Pkm1 KD alters the localization of nuclear Dpf2 into the cytoplasm as well. Mechanistically, Pkm KD resulted in decreased binding of cBAF components to their myogenic target genes, which also suggested a positive regulation between the cBaf complex and the H3 phosphorylation marks.

2024-05-01 | GSE252751 | GEO

EWS-FLI1 modulated alternative splicing of ARID1A reveals novel oncogenic function through the BAF complex

Project description:There is a long-established connection between epigenetic reprogramming and the local function of the spliceosome. Recently the oncogenic potential of this connection has also been recognized. Recent work has demonstrated that EWS-FLI1 recruits the BRG1/BRM-associated factor (BAF) complex, however, the specific BAF subunits that interact with EWS-FLI1 and the role of the BAF complex in oncogenesis remains unknown. Within the BAF complex, the AT-rich interactive domain-containing protein 1A (ARID1A, BAF250a) gene encodes a central scaffold. EWS-FLI1 is a well-described transcriptional regulator that also has a role in modulating RNA splicing. While EWS-FLI1 alters the splicing of many mRNA isoforms, the role of splicing modulation in ES oncogenesis remains unknown. Here we report a direct connection between the EWS-FLI1-induced transcriptome and the EWS-FLI1 protein interactome to reveal a novel interaction with a specific isoform of ARID1A that has a direct impact on oncogenicity. We report a novel feed-forward cycle of EWS-FLI1 and ARID1A-L facilitating ES growth through splicing modulation and protein stability that may lead to improved cancer-specific drug targeting.

2019-08-30 | GSE115676 | GEO

ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas

Project description:We have sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWIâ€“SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas

| EGAS00000000075 | EGA

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