STUB1-mediated K63-linked ubiquitination of UHRF1 promotes the progression of cholangiocarcinoma by maintaining DNA hypermethylation of PLA2G2A
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ABSTRACT:
PROVIDER: PRJNA1151045 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30344266_1.fastq.gz | Fastqsanger.gz | |||
| SRR30344266_2.fastq.gz | Fastqsanger.gz | |||
| SRR30344267_1.fastq.gz | Fastqsanger.gz | |||
| SRR30344267_2.fastq.gz | Fastqsanger.gz | |||
| SRR30344268_1.fastq.gz | Fastqsanger.gz |
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Project description:Cholangiocarcinoma (CCA) is a highly malignant tumor characterized by a lack of effective targeted therapeutic strategies. The protein UHRF1 plays a pivotal role in the preservation of DNA methylation and works synergistically with DNMT1. Posttranscriptional modifications (PTMs), such as ubiquitination, play indispensable roles in facilitating this process. Nevertheless, the specific PTMs that regulate UHRF1 in CCA remain unidentified. We confirmed the interaction between STUB1 and UHRF1 through mass spectrometry analysis. Furthermore, we investigated the underlying mechanisms of the STUB1-UHRF1/DNMT1 axis via co-IP experiments, denaturing IP ubiquitination experiments, nuclear‒cytoplasmic separation and immunofluorescence experiments. STUB1-UHRF1/DNMT1-mediated DNA methylation plays a crucial role in promoting the epigenetic silencing of tumor suppressor genes (TSGs) and facilitating tumor progression. To investigate the specific TSGs regulated by the STUB1-UHRF1/DNMT1 axis in CCA cells, RNA-seq analysis of overexpressed STUB1 and negative control TFK1 cells was performed.
2024-09-16 | GSE275480 | GEO
Project description:RNA interference (RNAi) is a cell-intrinsic antiviral defense conserved in diverse organisms. However, the mechanism by which mammalian antiviral RNAi is regulated is largely unknown. Herein, we uncover that STUB1, an E3 ubiquitin ligase, interacts with and ubiquitinates AGO2, the core component of RNAi pathway, resulting in the degradation of AGO2 via ubiquitin-proteasome system. Additionally, STUB1 can induce the degradation of the other mammalian AGO proteins including AGO1, AGO3, and AGO4. Our further study reveals that STUB1 also interacts with and mediates the ubiquitination of Dicer, the endoribonuclease responsible for siRNA or miRNA biogenesis, via K48-linked poly-ubiquitin, which induces the degradation of Dicer and its specialized form, termed antiviral Dicer (aviDicer) that usually expresses in stem cells. Loss of STUB1 upregulated Dicer and AGO2, thereby enhancing antiviral RNAi to effectively inhibit viral RNA replication in mammalian cells. In vivo, the STUB1 deficiency markedly enhanced the production of virus-derived siRNAs and elicited a potent antiviral effect against Enterovirus-A71 (EV-A71) infection in newborn mouse. Our findings demonstrate STUB1 as a novel negative regulator of RNAi by mediating the ubiquitination and degradation of Dicer and AGO proteins, and provide novel insights into the regulatory mechanism of antiviral RNAi in mammals.
2021-11-22 | GSE189203 | GEO
Project description:TBK1 plays a pivotal role in innate antiviral immunity, serving as a critical mediator downstream of various pattern recognition receptors (PRRs). TBK1 activity is tightly regulated by post-translational modifications (PTMs) including ubiquitination to maintain innate immune homeostasis. Here, we identify the Deltex E3 ubiquitin ligase 2 (DTX2) as a positive regulator of innate antiviral signaling in response to RNA viruses. We find that DTX2 overexpression enhances antiviral signaling, whereas loss of DTX2 evidently reduces antiviral responses. Mechanistically, we demonstrated that DTX2 directly interacts with TBK1 and promotes TBK1 K63-linked polyubiquitination to regulate antiviral signaling. Collectively, our study reveals that DTX2 plays a novel positive regulatory role in antiviral signaling by modulating the K63-linked ubiquitination of TBK1 to maintain the balance of innate antiviral immune responses.
2025-01-04 | GSE285743 | GEO
Project description:DNA methylation and histone lysine tri-methylation at H3K27 (H3K27me3) are the two primary epigenetic marks for transcriptional silencing essential for cell fate determination and cell lineage commitment during development1, 2. These two marks are mutually exclusive and target distinct sets of genes in the mammalian genome3. However, whether and how H3K27me3 shapes the DNA methylome remains unknown. Here, we report that the loss of H3K27me3 modification leads to increased DNA methylation at previously marked H3K27me3 sites, revealing that H3K27me3 negatively regulates DNA methylation. Genome-wide analysis of H3 ubiquitination, essential for recruitment and activation of DNA methyltransferase DNMT14, reveals the absence of H3 ubiquitination at H3K27me3 marked nucleosomes. Moreover, loss of H3K27me3 modification induces an increase in H3K18 ubiquitination at the corresponding hypermethylated loci. Importantly, we show that H3K27me3 directly inhibits UHRF1-mediated H3 ubiquitination toward nucleosomes in a defined biochemical assay. Furthermore, UHRF1 is required for the increase in DNA methylation at previously marked H3K27me3 sites in cells with abolished H3K27me3 modification. Taken together, our findings reveal a general mechanism for H3K27me3-mediated shaping of the mammalian DNA methylome via modulation of H3 ubiquitination.
2022-06-27 | GSE159041 | GEO
Project description:DNA methylation and histone lysine tri-methylation at H3K27 (H3K27me3) are the two primary epigenetic marks for transcriptional silencing essential for cell fate determination and cell lineage commitment during development1, 2. These two marks are mutually exclusive and target distinct sets of genes in the mammalian genome3. However, whether and how H3K27me3 shapes the DNA methylome remains unknown. Here, we report that the loss of H3K27me3 modification leads to increased DNA methylation at previously marked H3K27me3 sites, revealing that H3K27me3 negatively regulates DNA methylation. Genome-wide analysis of H3 ubiquitination, essential for recruitment and activation of DNA methyltransferase DNMT14, reveals the absence of H3 ubiquitination at H3K27me3 marked nucleosomes. Moreover, loss of H3K27me3 modification induces an increase in H3K18 ubiquitination at the corresponding hypermethylated loci. Importantly, we show that H3K27me3 directly inhibits UHRF1-mediated H3 ubiquitination toward nucleosomes in a defined biochemical assay. Furthermore, UHRF1 is required for the increase in DNA methylation at previously marked H3K27me3 sites in cells with abolished H3K27me3 modification. Taken together, our findings reveal a general mechanism for H3K27me3-mediated shaping of the mammalian DNA methylome via modulation of H3 ubiquitination.
2022-06-27 | GSE159040 | GEO
Project description:DNA methylation and histone lysine tri-methylation at H3K27 (H3K27me3) are the two primary epigenetic marks for transcriptional silencing essential for cell fate determination and cell lineage commitment during development1, 2. These two marks are mutually exclusive and target distinct sets of genes in the mammalian genome3. However, whether and how H3K27me3 shapes the DNA methylome remains unknown. Here, we report that the loss of H3K27me3 modification leads to increased DNA methylation at previously marked H3K27me3 sites, revealing that H3K27me3 negatively regulates DNA methylation. Genome-wide analysis of H3 ubiquitination, essential for recruitment and activation of DNA methyltransferase DNMT14, reveals the absence of H3 ubiquitination at H3K27me3 marked nucleosomes. Moreover, loss of H3K27me3 modification induces an increase in H3K18 ubiquitination at the corresponding hypermethylated loci. Importantly, we show that H3K27me3 directly inhibits UHRF1-mediated H3 ubiquitination toward nucleosomes in a defined biochemical assay. Furthermore, UHRF1 is required for the increase in DNA methylation at previously marked H3K27me3 sites in cells with abolished H3K27me3 modification. Taken together, our findings reveal a general mechanism for H3K27me3-mediated shaping of the mammalian DNA methylome via modulation of H3 ubiquitination.
2022-06-27 | GSE159042 | GEO
Project description:Besides ectodermal derivatives morphogenesis, the inactivation of the Ectodysplasin A(EDA)/Ectodysplasin A Receptor(EDAR) signaling pathway has also been demonstrated to impede the process of skin repair. EDAR, a member of the tumor necrosis factor receptor superfamily, plays a central role in this signaling pathway.However, the regulatory mechanism of EDAR and its target genes in wound healing remain unclear.As a membrane protein, the turnover of EDAR is more likely to be affected by ubiquitination, where an E3 Ubuitin ligase targets substrates for degradation. We performed a yeast two-hybrid assay to identify the potential E3 ligase. STIP1 homology and U-box-containing protein 1 (STUB1) was found to interact with EDAR and mediate its ubiquitination and degradation. To explore the function of STUB1 in keratinocytes, we constructed STUB1 knockout HaCaT cells, which showed accelerated healing and growth capabilities. Elevated protein level of EDAR and upregulated activation of downstream nuclear factor-κB signaling were detected in STUB1 knockout HaCaT cells. To find out why STUB1 knockout induced the functional alteration of HaCaT cells and which genes might be affected, an RNA-seq analysis was performed.
2025-01-18 | GSE280408 | GEO
Project description:The reversible attachment of ubiquitin governs the interaction, activity and degradation of proteins whereby the type and target of this conjugation determine the biological response. The investigation of this complex and multi-faceted protein ubiquitination mostly relies on painstaking biochemical analyses. Here, we employ recombinant binding domains to identify the UHRF1 dependent ubiquitinated proteins by liquid chromatography tandem mass spectrometry (LC-MS/MS).
2023-01-30 | PXD034335 | Pride
Project description:H3K27me3 shapes DNA methylome by inhibiting UHRF1-mediated H3 ubiquitination
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Project description:The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about 36 regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identified STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This was corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response was increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.
2022-03-07 | PXD030580 | Pride