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RNA-seq in shControl Huh7 and shARID1A Huh7 cells without or with rapamycin treatment

ABSTRACT: mTORC1 is a conserved central controller of cell growth, which is commonly activated in hepatocellular carcinoma (HCC), driving liver tumorigenesis. In addition to its established cytoplasmic functions, mTORC1 is found in the nucleus where it regulates transcription by all three major RNA polymerases. However, precisely how mTORC1 controls gene expression remains poorly understood. Herein we show that mTORC1 interacts with the BAF SWI/SNF complex and regulates genome-wide chromatin remodeling through ARID1A. Mechanically, mTORC1 stimulates ubiquitination and proteasomal degradation of ARID1A protein through SCF ubiquitin ligase. mTORC1-ARID1A axis promotes chromatin remodeling and expression of YAP target genes, thereby enhancing oncogenic growth in vitro and in vivo. These findings reveal a novel nuclear mTORC1 function and the underlying mechanism that controls oncogenic chromatin remodeling to promote hepatocarcinogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE159164 | GEO | 2021/04/01

REPOSITORIES: GEO

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ATAC-seq in shControl Huh7 and shARID1A Huh7 cells without or with rapamycin treatment

Project description:mTORC1 is a conserved central controller of cell growth, which is commonly activated in hepatocellular carcinoma (HCC), driving liver tumorigenesis. In addition to its established cytoplasmic functions, mTORC1 is found in the nucleus where it regulates transcription by all three major RNA polymerases. However, precisely how mTORC1 controls gene expression remains poorly understood. Herein we show that mTORC1 interacts with the BAF SWI/SNF complex and regulates genome-wide chromatin remodeling through ARID1A. Mechanically, mTORC1 stimulates ubiquitination and proteasomal degradation of ARID1A protein through SCF ubiquitin ligase. mTORC1-ARID1A axis promotes chromatin remodeling and expression of YAP target genes, thereby enhancing oncogenic growth in vitro and in vivo. These findings reveal a novel nuclear mTORC1 function and the underlying mechanism that controls oncogenic chromatin remodeling to promote hepatocarcinogenesis.

2021-04-01 | GSE159163 | GEO

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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Proteome analyses of two ovarian clear cell carcinoma cell lines with or without ARID1A manipulation

Project description:ARID1A, which encodes a component of the SWI/SNF chromatin-remodeling complex, is commonly mutated in ovarian clear cell carcinoma and many other cancer types. We used label-free LC-MS/MS to identify ARID1A-dependent proteome changes in ovarian clear cell carcinoma cell lines. In our first analysis, we compared ARID1A-wildtype ovarian clear cell carcinoma cell line OVCA429 with or without ARID1A CRISPR knockout. In a complementary analysis, we compared ARID1A-mutated ovarian clear cell carcinoma cell line OVISE with or without ARID1A overexpression using a tet-inducible promoter.

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Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks driven by IRF4. To discover unique molecular vulnerabilities in MM centered on IRF4, we employ a multi-omics approach integrating functional genomics screening, spatial proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, therefore defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease have markers of SWI/SNF activity, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path to effectively treat this incurable disease.

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Phase Separation of ARID1A Chromatin Remodeling Factor Promotes Oncogenic Potential of Ewing’s Sarcoma

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ARID1A regulates transcription and the epigenetic landscape via POLE and DMAP1 while ARID1A deficiency or pharmacological inhibition sensitizes germ cell tumor cells to ATR inhibition

Project description:Germ cell tumors (GCTs) are the most common solid malignancies in young men. Although high cure rates can be achieved at early stages, metastases, resistance to cisplatin-based therapy, and late toxicities still represent a lethal threat, arguing for the need of new therapeutic options. In a previous study, we identified downregulation of the chromatin-remodeling SWI/SNF complex member ARID1A as a key event in the mode of action of the histone deacetylase inhibitor romidepsin, subsequently leading to induction of stress, apoptosis and cell cycle regulators. Additionally, ARID1A is mutated in many different tumor types, like bladder, breast or ovarial cancer. There, the loss-of-function mutations re-sensitize these tumor types to various drugs, like EZH2-, PARP-, HDAC-, HSP90- or ATR-inhibitors. Thus, ARID1A presents as a promising target for synthetic lethality and combination therapy. In this study, we deciphered the molecular function of ARID1A and screened for the potential of two pharmacological ARID1A inhibitors as a new therapeutic strategy to treat GCTs. By CRISPR/Cas9, we generated ARID1A-deficient GCT cells and demonstrate that ARID1A regulates transcription, DNA repair and the epigenetic landscape on DNA and histone level via DNA Polymerase POLE and the DNA methyltransferase 1-associated protein DMAP1. Additionally, ARID1A deficiency or pharmacological inhibition considerably sensitized (cisplatin-resistant) GCT cells towards ATR inhibition. Thus, ARID1A might be new combination partner for ATR inhibitors in the treatment of GCTs.

2020-04-14 | PXD017898 | Pride

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

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 | GSE106662 | GEO

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

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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]

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A CRISPR/Cas9-engineered ARID1A-deficient human gastric cancer organoid model reveals essential and non-essential modes of oncogenic transformation

Project description:Mutations in ARID1A, encoding a subunit of the BAF chromatin remodeling complex, rank amongst the most common molecular aberrations in human cancer. However, oncogenic consequences of ARID1A mutation in human cells remain poorly defined due to lack of forward human genetic model systems. Here, CRISPR/Cas9 knockout of ARID1A in primary TP53-/- human gastric organoids induced morphologic dysplasia, tumorigenicity and mucinous differentiation but impaired Wnt/b-catenin signaling. Genetic Wnt pathway activation rescued mucinous differentiation, but not hyperproliferation, suggesting alternative essential pathways of ARID1A-mediated transformation. ARID1A loss induced transcriptional regulatory modules characteristic of MSI and EBV subtype human gastric cancer, including FOXM1 regulation of multiple mitotic regulatory genes and BIRC5/survivin. Convergently, high-throughput compound screening indicated selective vulnerability of ARID1A-deficient organoids to BIRC5/survivin inhibition, functionally implicating BIRC5/survivin as an essential mediator of proliferation following initial ARID1A loss. However, CRISPR inactivation of ARID1A in established gastric cancer cell lines did not elicit sensitivity to BIRC5/survivin inhibitors, suggesting that this pathway may be selectively required during the early establishment of tumorigenesis. Overall, we define distinct pathways downstream of oncogenic ARID1A mutation, with non-essential Wnt-inhibited mucinous differentiation in parallel with essential transcriptional FOXM1/BIRC5-stimulated proliferation, indicating the general utility of organoid-based forward genetic cancer analysis in human cells.

2021-01-05 | GSE164179 | GEO

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