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Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription.

ABSTRACT: The ARID1A subunit of the SWI/SNF chromatin remodelling complex is one of the most frequently mutated tumour suppressors. Here, a degron system is applied to detect rapid loss of chromatin accessibility at thousands of loci that frequently include binding sites for pluripotency transcription factors where ARID1A acts to generate accessible mini domains of nucleosomes. At a subset of these locations, the histone acetyltransferase EP300 dissociates and histone H3K27 acetylation decreases. Genes adjacent to these sites are frequently downregulated. Remarkably, dissociation of EP300 in the absence of chromatin changes is linked to rapid transcriptional upregulation. Sites where EP300 exhibits co-repressor activity are enriched for MLL3-4, BRD4 and RNA polymerase. A few genes directly affected by these pathways are associated with cancer and pluripotency pathways that come to dominate the chronic ARID1A phenotype. This suggests a handful of upstream regulators drive adaption and represent new sites for intervention in ARID1A driven diseases.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Embryonic Stem Cell

SUBMITTER: Nicola Wiechens

LAB HEAD: Tom Owen-Hughes

PROVIDER: PXD021623 | Pride | 2021-11-02

REPOSITORIES: Pride

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			Action	DRS
	OxidationMSites.txt	Txt
	SAG-ARIDIA-0-1.raw	Raw
	SAG-ARIDIA-0-2.raw	Raw
	SAG-ARIDIA-0-3.raw	Raw
	SAG-IgG-1.raw	Raw

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Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription

Project description:The ARID1A subunit of the SWI/SNF chromatin remodelling complex is one of the most frequently mutated tumour suppressors. Here, a degron system is applied to detect rapid loss of chromatin accessibility at thousands of loci that frequently include binding sites for pluripotency transcription factors where ARID1A acts to generate accessible mini domains of nucleosomes. At a subset of these locations, the histone acetyltransferase EP300 dissociates and histone H3K27 acetylation decreases. Genes adjacent to these sites are frequently downregulated. Remarkably, dissociation of EP300 in the absence of chromatin changes is linked to rapid transcriptional upregulation. Sites where EP300 exhibits co-repressor activity are enriched for MLL3-4, BRD4 and RNA polymerase. A few genes directly affected by these pathways are associated with cancer and pluripotency pathways that come to dominate the chronic ARID1A phenotype. This suggests a handful of upstream regulators drive adaption and represent new sites for intervention in ARID1A driven diseases.

2021-11-02 | PXD021824 | Pride

Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription.

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Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription.

2021-11-02 | PXD021624 | Pride

Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription.

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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.

2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress

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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Project description:This study identifies binding sites for the chromatin remodeller subunit ARID1A in the HCT116 colorectal cancer cell line.

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Investigation of DNA double-strand break repair mechanisms in microsatellite regions using the CRISPR/Cas9 system

Project description:Expansion of the CAG/CTG repeats in functionally unrelated genes is a causative factor in many inherited neurodegenerative disorders, including Huntington's disease (HD), spinocerebellar ataxias (SCAs) and myotonic dystrophy type 1 (DM1). Despite many years of research, the mechanism responsible for repeat instability is unknown, and recent findings indicate the key role of DNA repair in this process. The repair of DSBs induced by genome editing tools results in the shortening of long CAG repeats in yeast models. Understanding this mechanism is the first step to developing a therapeutic strategy based on controlled shortening of repeats. The aim of this study was to characterize Cas9-induced DSB repair products in the endogenous HTT locus in human cells and to identify factors affecting the formation of specific types of mutations. The location of the cleavage site and its sequence affect the outcome of DNA repair. DSBs within CAG repeats result in shortening of the repeats in frame in ~90% of products. The mechanism of this contraction involves MRE11-CTIP and RAD51 activity and extensive DNA end resection reaching ~5000 bp. We demonstrated that a DSB located upstream of CAG repeats induces polymerase theta-mediated end joining, resulting in deletion of the entire CAG tract. Furthermore, using unbiased proteomic analysis, we identified novel factors that may be involved in CAG sequence repair.

2024-11-04 | PXD044960 | Pride

Proteomic profile of saliva in Parkinson’s disease patients.

Project description:Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Lewy pathology involves numerous organs. Submandibular glands are affected in about 75% of in vivo cases, with higher rates of positive findings in post-mortem histopathological studies. Salivary microbiome composi-tion in PD patients is also different than in healthy patients. Therefore, we hypothesize that saliva may serve as a potential source of biomarkers of Parkinson’s disease. To evaluate and compare the salivary proteome of PD patients and healthy controls (HC). Salivary samples from 39 subjects (24 PD patients mean age 61.6 8.2 and 15 HC mean age 60.96.7) were used. Saliva was collected 30 minutes after rinsing mouth with tap water, in the morning hours, using RNA-Pro-Sal kits. Samples were immediately frozen at -80oC after collection. Label-free LC-MS/MS mass spectrometry was performed to comprehensively characterize the proteome of the saliva. IPA analysis of upstream inhibitors was performed. A total of 530 proteins and peptides were identified. We observed significantly lower concentrations of S100-A16, ARP2/3 and VPS4B in PD group vs controls. Additional IPA analysis indicated PD98059 to be most significantly activated and beta-estradiol most significantly inhibited upstream regulators. Conclusions: Very limited data on the salivary proteome of PD subjects is available. The results of our analysis indicate that the salivary proteome of PD patients might be different than that of healthy controls. We observed significantly lower concentrations of proteins involved in inflammatory processes, exosome formation and adipose tissue formation among others. Upstream regulator analysis indicated several proteins previously associated with neurodegeneration to drive the differential protein expression in saliva. The main limitations of the study are variability of expression of proteins between subjects in the two groups and variations caused by external factors.

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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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