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

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

PROVIDER: PRJNA1072107 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27840836_1.fastq.gz	Fastqsanger.gz
	SRR27840836_2.fastq.gz	Fastqsanger.gz
	SRR27840837_1.fastq.gz	Fastqsanger.gz
	SRR27840837_2.fastq.gz	Fastqsanger.gz
	SRR27840838_1.fastq.gz	Fastqsanger.gz

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

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

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

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

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

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PPP2R1A mutations cause ATR inhibitor synthetic lethality in ARID1A deficient ovarian clear cell carcinoma

Project description:Ovarian clear cell carcinoma (OCCC) is a cancer of unmet need characterized by ARID1A mutation. Prior work identified an ARID1A/ATR synthetic lethality, information that led to phase II clinical trials. Using genome-wide CRISPR-Cas9 mutagenesis and interference screens, we identified protein phosphatase 2A (PP2A) subunits, including PPP2R1A, as determinants of ATRi sensitivity in ARID1A mutant OCCC. Analysis of an OCCCs cohort indicated that >1/3 possessed both PPP2R1A and ARID1A loss-of-function mutations. CRISPR-prime editing demonstrated that oncogenic PPP2R1A p.R183 missense mutations enhance in vitro and in vivo ATRi sensitivity in ARID1A mutant OCCC. OCCC patients with both ARID1A and PPP2R1A mutations also showed clinical responses to ATRi in a phase II trial. Mechanistically, this synthetic lethal effect is dependent upon WNK1 kinase, which opposes PP2A function. This data suggests that co-occurrence of PPP2R1A and ARID1A mutations in OCCC should be assessed as a biomarker of ATRi response in on-going clinical trials.

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mRNA-seq for HCT116 Parental and ARID1A knockdown cells, mRNA-seq for DLD1 Parental, ARID1A knockdown and ARID1A knockout cells, mRNA-seq for COLO320DM Parental and ARID1A knockdown and ARID1A knockout cells

Project description:The study identifies genes that are regulated by the loss of the chromatin remodeller subunit ARID1A in colorectal cancer cell lines. This gene is frequently mutated in colorectal cancer.

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ChIP-seq analysis of Arid1a and C/ebpÎ± in the mouse livers

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/ebpÎ±, 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/ebpÎ± 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/ebpÎ± binds at precisely the same positions, indicating that Arid1a facilitates C/ebpÎ± binding across the genome. Perfuse and isolate primary hepatocytes from mice livers, analysis of genomic occupancy of C/ebpÎ± 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.

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Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.

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Gene expression data ARID1A knockdown OE33 cells versus mock OE33 cells

Project description:A nonsense mutation in ARID1A was identified by next generation sequencing in non-dysplastic Barrett's esophagus [BE] tissue and esophageal adenocarcinoma [EAC] tissue of a patient diagnosed with EAC. Immunohistochemistry performed on an independent archival cohort demonstrated ARID1A protein loss in 0% (0/76), 4.9% (2/40), 14.3% (4/28), 16.0% (8/50), and 12.2% (12/98) of normal squamous epithelium, BE, low-, high-grade dysplasia, and EAC tissues, respectively. Enhanced cell growth, proliferation and invasion were observed upon ARID1A knockdown in EAC cells. ARID1A was knocked down in OE33 cells (Sample MS_1 and MS_3) using on-TARGET smartpool ARID1A siRNA. At the same time, OE33 cells were transfected with a non-targeting siRNA, and these experiments (Samples MS_2 and MS_4) functioned as mock controls. Cells were harvested after 48 hours and total RNA was extracted using the Rneasy kit (Qiagen) Aim Affymetrix Human PrimeView Gene Expression Array : to determine the downstream effectors of ARID1A that are likely to contribute to the oncogenic phenotype caused by ARID1A down-regulation. Two biological replicates of each condition (2x ARID1A knockdown, and 2x Mock) were used for the microarray experiment.

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