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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: PXD021824 | Pride | 2021-11-02

REPOSITORIES: Pride

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			Action	DRS
	DeamidationNQSites.txt	Txt
	DioxidationMWSites.txt	Txt
	NW-ARID1A-1.raw	Raw
	NW-ARID1A-2.raw	Raw
	NW-ARID1A-3.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.

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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.

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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.

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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 | PXD021636 | Pride

Genome-wide analysis of effects of ARID1A depletion in mouse embryonic stem cells

Project description:A degron system is used to deplete ARID1A a subunit of the SWI/SNF complex in mouse embryonic stem cells. Genome wide analysis of chromatin accessibility (ATAC-seq), nucleosome posistioning (MNase-seq), nascent transcription (TT-seq), binding to EP300 and presence of histone H3 K27acetylation (ChIP-seq) amd histone H3K27 tria-methylation (ChIP-seq) allowed us to identify two different pathways responsible for the up and downregulation of transcription following the loss of ARID1A. The rapid depletion of ARID1A generates mini domains of nucleomes at pluripotency transcription factor binding sites. Loss of ARID1A also results in the redistribution of the co-activator EP300. Locations of co-incident EP300 dissociation and lost chromatin accessibility occur adjacent to rapidly downregulated genes. Promoter proximal regions that gain EP300 are linked to genes that are transcriptionally upregulated. Our findings illustrate the importance of both direct and indirect effects in causing rapid changes to gene expression. Only a few genes are directly affected after ARID1A depletion and contribute to pathways associated with cancer and pluripotency establishing the loss of ARID1A phenotype.

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ARID1A regulates chromatin organization and establishment of epigenetic marks for DSB repair and transcription silencing

Project description:AT-rich interactive domain-containing protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. ARID1A contributes to DNA damage response pathways, and we previously reported that ARID1A loss is associated with mutational signatures linked to DNA repair defects. Here we show that ARID1A is promoting both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates the chromatin loop formation at DSB sites by interacting with the cohesin subunit RAD21 and CTCF insulator protein promoting their enrichment around the DSBs. Further analysis demonstrates that ARID1A’s involvement in DSB repair is accompanied by alterations of chromatin accessibility and distribution of activating histone marks at DSBs. ARID1A binds to and promotes the recruitment of the HDAC1 to control transcription repression at these DSBs. Altogether, ARID1A simultaneously regulates DSB repair and transcription silencing in transcriptionally active chromatin. ARID1A depletion resulted in defective DSB repair, which subsequently led to accumulation of micronuclei, activation of cGAS-STING pathway and an increased expression of immunomodulatory cytokines and chemokines upon IR treatment. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and can estimate the levels of tumor-infiltrating immune cells and response to combination of radio- and immunotherapy.

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2024-12-10 | PXD050374 | Pride

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.

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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.

2022-10-14 | PXD023489 | Pride

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders

Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.

2021-10-12 | PXD028557 | Pride

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