Multidimensional OMICs reveal ARID1A orchestrated control of DNA damage, splicing, and cell cycle in normal and malignant urothelial cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE271687 | GEO | 2025/03/04
REPOSITORIES: GEO
Similar Datasets
Project description:Epigenetic regulators, such as the SWI/SNF complex, play an important role in tissue development and homeostasis, and are frequently mutated in cancer. ARID1A, a subunit of the SWI/SNF complex, is mutated in approximately 20% of all bladder tumors, however, our understanding of the consequences thereof remains limited. Finding truncations to be the most common mutation, we generated loss- and gain-of-function models to conduct RNA-Seq, interactome analyses, Omni-ATAC-Seq, and first functional studies to characterize ARID1A-affected pathways potentially suitable for the treatment of ARID1A-deficient bladder cancers. We observed decreased cell proliferation and deregulation of stress-regulated pathways, including DNA repair in ARID1A-deficient cells. Furthermore, ARID1A was linked to alternative splicing and translational regulation on RNA and interactome levels. ARID1A deficiency drastically reduced the accessibility of chromatin, especially around introns and distal, but not proximal, enhancers. Less accessible chromatin areas were mapped to pathways such as cell proliferation and DNA damage response. Indeed, the G2/M checkpoint appeared impaired after DNA damage in ARID1A-deficient cells. Together, this highlights the broad impact of ARID1A and the possibility of targeting proliferative and DNA repair pathways.
2025-03-02 | PXD054817 | Pride
Project description:Epigenetic regulators, such as the SWI/SNF complex, play an important role in tissue development and homeostasis, and are frequently mutated in cancer. ARID1A, a subunit of the SWI/SNF complex, is mutated in approximately 20% of all bladder tumors, however, our understanding of the consequences thereof remains limited. Here, we generated various loss- and gain-of-function models to conduct Omni-ATAC-Seq, RNA-Seq, interactome analyses, and first functional studies to characterize ARID1A-affected pathways potentially suitable for the treatment of ARID1A-deficient bladder cancers. We observed decreased cell proliferation and deregulation of stress-regulated pathways including DNA repair in ARID1A-deficient cells. Furthermore, ARID1A was linked to alternative splicing and translational regulation on RNA and interactome levels. The absence of ARID1A drastically impacted the accessibility of chromatin, displaying significantly less accessible chromatin especially around distal, but not proximal, enhancers. Less accessible chromatin areas were mapped to pathways such as DNA damage response and cell proliferation. Indeed, the G2/M checkpoint appeared impaired after DNA damage in ARID1A-deficient cells. Together, this highlights the broad impact of ARID1A and the possibility of targeting proliferative and DNA repair pathways.
2025-03-04 | GSE271587 | GEO
Project description:Epigenetic regulators, such as the SWI/SNF complex, play an important role in tissue development and homeostasis, and are frequently mutated in cancer. ARID1A, a subunit of the SWI/SNF complex, is mutated in approximately 20% of all bladder tumors, however, our understanding of the consequences thereof remains limited. Here, we generated various loss- and gain-of-function models to conduct Omni-ATAC-Seq, RNA-Seq, interactome analyses, and first functional studies to characterize ARID1A-affected pathways potentially suitable for the treatment of ARID1A-deficient bladder cancers. We observed decreased cell proliferation and deregulation of stress-regulated pathways including DNA repair in ARID1A-deficient cells. Furthermore, ARID1A was linked to alternative splicing and translational regulation on RNA and interactome levels. The absence of ARID1A drastically impacted the accessibility of chromatin, displaying significantly less accessible chromatin especially around distal, but not proximal, enhancers. Less accessible chromatin areas were mapped to pathways such as DNA damage response and cell proliferation. Indeed, the G2/M checkpoint appeared impaired after DNA damage in ARID1A-deficient cells. Together, this highlights the broad impact of ARID1A and the possibility of targeting proliferative and DNA repair pathways.
2025-03-04 | GSE271301 | GEO
Project description:Multidimensional OMICs reveal ARID1A orchestrated control of DNA damage, splicing, and cell cycle in normal and malignant urothelial cells
| PRJNA1132912 | ENA
Project description:Multidimensional OMICs reveal ARID1A orchestrated control of DNA damage, splicing, and cell cycle in normal and malignant urothelial cells [ATAC-seq]
| PRJNA1132254 | ENA
Project description:Multidimensional OMICs reveal ARID1A orchestrated control of DNA damage, splicing, and cell cycle in normal and malignant urothelial cells [RNA-seq]
| PRJNA1130888 | ENA
Project description:Changes in the cellular environment result in chromatin structure alteration, which in turn regulates gene expression. To learn about the effect of the cellular environment on the transcriptome, we studied the H3K9 demethylase KDM3A. Using RNA-seq, we found that KDM3A regulates the transcription and alternative splicing of genes associated with cell cycle and DNA damage. We showed that KDM3A undergoes phosphorylation by PKA at serine 265 following DNA damage, and that the phosphorylation is important for proper cell-cycle regulation. We demonstrated that SAT1 alternative splicing, regulated by KDM3A, plays a role in cell-cycle regulation. Furthermore we found that KDM3A's demethylase activity is not needed for SAT1 alternative splicing regulation. In addition, we identified KDM3A's protein partner ARID1A, the SWI/SNF subunit, and SRSF3 as regulators of SAT1 alternative splicing and showed that KDM3A is essential for SRSF3 binding to SAT1 pre-mRNA. These results suggest that KDM3A serves as a sensor of the environment and an adaptor for splicing factor binding. Our work reveals chromatin sensing of the environment in the regulation of alternative splicing.
| S-EPMC8522690 | biostudies-literature
Project description:ARID1a (BAF250), a component of human SWI/SNF chromatin remodeling complexes, is frequently mutated across numerous cancers, and its loss of function has been putatively linked to glucocorticoid resistance. Here, we interrogate the impact of siRNA knockdown of ARID1a compared to a functional interference approach in the HeLa human cervical cancer cell line. We report that ARID1a knockdown resulted in a significant global decrease in chromatin accessibility in ATAC-Seq analysis, as well as affecting a subset of genome-wide GR binding sites determined by analyzing GR ChIP-Seq data. Interestingly, the specific effects on gene expression were limited to a relatively small subset of glucocorticoid-regulated genes, notably those involved in cell cycle regulation and DNA repair. The vast majority of glucocorticoid-regulated genes were largely unaffected by ARID1a knockdown or functional interference, consistent with a more specific role for ARID1a in glucocorticoid function than previously speculated. Using liquid chromatography-mass spectrometry, we have identified a chromatin-associated protein complex comprising GR, ARID1a, and several DNA damage repair proteins including P53 binding protein 1 (P53BP1), Poly(ADP-Ribose) Polymerase 1 (PARP1), DNA damage-binding protein 1 (DDB1), DNA mismatch repair protein MSH6 and splicing factor proline and glutamine-rich protein (SFPQ), as well as the histone acetyltransferase KAT7, an epigenetic regulator of steroid-dependent transcription, DNA damage repair and cell cycle regulation. Not only was this protein complex ablated with both ARID1a knockdown and functional interference, but spontaneously arising DNA damage was also found to accumulate in a manner consistent with impaired DNA damage repair mechanisms. Recovery from dexamethasone-dependent cell cycle arrest was also significantly impaired. Taken together, our data demonstrate that although glucocorticoids can still promote cell cycle arrest in the absence of ARID1a, the purpose of this arrest to allow time for DNA damage repair is hindered.
| S-EPMC9734058 | biostudies-literature
Project description:ObjectiveAT-rich interactive domain-containing protein 1A (ARID1A) is frequently mutated or deficient in various types of tumors. However, the role of ARID1A in bladder cancer remains unclear. We aimed to evaluate ARID1A expression and its biological role and correlation with prognosis in patients with urothelial bladder carcinoma (BUC).MethodsARID1A expression levels in BUC and normal tissues were assessed by immunohistochemistry and correlated with clinicopathological characteristics and patient outcomes. Downregulation of ARID1A was mimicked by transfection with small interfering RNA in T24 bladder cancer cells, and the effects on cell proliferation and migration were evaluated.ResultsARID1A expression was significantly reduced in BUC tissues and was significantly associated with T stage and AJCC stage. Upregulation of ARID1A predicted a better prognosis in BUC patients. ARID1A expression and lymph node status were identified as independent prognostic factors for overall survival. Silencing of ARID1A promoted the proliferation of BUC cells.ConclusionsARID1A may represent a novel diagnostic and prognostic biomarker in patients with BUC.
| S-EPMC7783253 | biostudies-literature
Project description:The presence of introns within otherwise completely spliced mRNA molecules has been associated with splicing errors. Recent evidence however suggests that intron-based transcript inactivation is widespread and regulates the cytoplasmic availability of productive transcript isoforms. The regulatory and functional details of this process have remained unclear. We here present the arginine methyltransferase Prmt5 as the top hit from an in vivo RNAi screen for therapeutic vulnerabilities of malignant gliomas. Inhibition of Prmt5 inactivates hundreds of pro-proliferative genes by increasing the inclusion of so-called “detained” introns (DIs) within mRNAs. DI-based inactivation of these genes causes cessation of cell proliferation and exhibits potent anti-tumor effects in vitro and in vivo. Gliomas become increasingly sensitive to Prmt5 inhibition upon tumor progression. Furthermore, DI-based gene expression regulation is not restricted to cancer, but contributes to cell differentiation by governing the expression levels of gene sets related to both cell cycle and cell identity.
2017-09-29 | GSE93813 | GEO