KIAA1429/VIRMA promotes breast cancer proliferation and migration by stabilizing m6A-modified HAS2 RNA expression in cytosol
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ABSTRACT:
PROVIDER: PRJNA769276 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16230400.fastq.gz | Fastqsanger.gz | |||
| SRR16230401.fastq.gz | Fastqsanger.gz | |||
| SRR16230402_1.fastq.gz | Fastqsanger.gz | |||
| SRR16230402_2.fastq.gz | Fastqsanger.gz | |||
| SRR16230403_1.fastq.gz | Fastqsanger.gz |
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Project description:N6-methyladenosine (m6A) is the most abundant internal RNA modification in mRNA molecules and plays important roles in multiple important biological processes including cancer development. KIAA1429/VIRMA is an important component of m6A methyltransferase complex to facilitate depositing m6A modification in RNA molecules. Here we found that KIAA1429/VIRMA was overexpressed in breast cancer patients among other m6A related enzymes. Breast cancer patients with higher KIAA1429 expression have worse survival compared with control group. In addition, KIAA1429/VIRMA protein mislocated in cytosol in breast cancer tissues and cell lines. KIAA1429/VIRMA depletion reduced breast cancer cell proliferation and migration. Mechanism studies showed that cytosolic expressed KIAA1429/VIRMA interacted with m6A reader protein IGF2BP3 and stabilized expression of m6A-modified HAS2 expression. HAS2 is downstream of KIAA1429/VIRMA to mediate breast cancer cell proliferation and migration and has positive correlation with KIAA1429/VIRMA expression in cancer patients.
2021-11-02 | GSE185494 | GEO
Project description:Analysis of hepatic stellate cells (HSCs) isoltaed from ASMA-HAS2 transgenic and HSC-specific Has2 knockout mice. HAS2 synthesized hyaluronic acid, one of major extracellular matrix. Results provide insight into the role of HAS2 in hepatic stellate cells.
2020-01-01 | GSE108593 | GEO
Project description:Background: HAS2 is a member of the gene family encoding hyaluronan synthase 2 (HAS2) which can generate high molecular weight hyaluronan (HMW-HA). Although we previously reported that HAS2 is a novel candidate gene for susceptibility to adult asthma., little is known about whether HAS2 dysfunction affect eosinophilic airway inflammation. Objective: We therefore hypothesized that attenuation of HAS2 will enhance eosinophilic airway inflammation. Methods: C57BL/6 wild type (WT) mice, Has2 heterozygous deficient (Has2+/−) mice were used in eosinophilic airway inflammation model which induced by ovalbumin (OVA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to detect Has2 and HA binding protein mRNA expression levels. Lung tissue and lavage fluid (BALF) were analyzed for inflammation and various cytokines and chemokines. Airway resistance was measured using forced oscillation technique. gene expression analyses were also performed to elucidate further pathogenesis. Results: The expression levels of Has2 mRNA was significantly decreased in OVA stimulated Has2+/− (Has2+/−-OVA) mice. Has2+/−-OVA mice also displayed significant reduce of CD44, and TGF-beta1 mRNA expression. BALF eosinophil number, levels of various Th2 cytokines and chemokines in BALF, and airway responsiveness were significantly increased in Has2+/−-OVA mice compared with similarly treated WT mice. ILK Signaling and PKA signaling were downregulated significantly more in Has2+/−-OVA mice compared with similarly treated WT mice. Conclusions: Has2 dysfunction induce more intense allergic eosinophilic airway inflammation and increase of airway hyper responsiveness with impairment of HAS2-CD44-TGF-beta signaling. Modulating HAS2 signaling might provide novel therapeutic targets for intractable bronchial asthma patients.
2022-04-04 | GSE148161 | GEO
Project description:Background: HAS2 is a member of the gene family encoding hyaluronan synthase 2 (HAS2), which can generate high-molecular-weight hyaluronan (HMW-HA). Our previous study identified HAS2 as a candidate gene for susceptibility to adult asthma. However, little is known if HAS2 dysfunction affects airway remodeling and steroid insensivity. In this study, we clarified the dysfunction of Has2 triggering severe airway remodeling and steroid insensitivity in a murine model of asthma. Methods: Ovalbumin (OVA) was used to induce eosinophilic airway inflammation and airway remodeling in Has2 heterozygous deficient (Has2+/−) mice and their wild-type (WT) littermates. Lung tissue histology, bronchoalveolar lavage fluid cell counting, quantitative PCR, HA size analysis, multiplex cytokines and chemokines analysis, RNA sequencing, anti IL-17 neutralization experiment were performed. Results: After chronic OVA stimulation, Has2+/− (Has2+/--OVA) mice showed significant decrease of Has2 mRNA expression levels, HMW-HA, HA-binding protein, and TGF-β. Has2+/--OVA mice demonstrated increased eosinophilic airway inflammation, goblet cell hyperplasia, and IL-17 levels. RNA sequencing demonstrated downregulation of EIF2 signaling pathways, TGF-β signaling pathways, and heat shock proteins with Th17 bias in Has2+/--OVA mice. Combined treatment with anti IL-17 antibody and dexamethasone reduce steroid insensitivity in Has2+/--OVA mice Conclusions: Has2 attenuation worsen eosinophilic airway inflammation, airway remodeling, and steroid insensitivity. This severe intractable phenotype might be induced by impairment of TGF-β signaling and ER stress response related signaling. These data highlight that HAS2 and HMW-HA are important for controlling intractable eosinophilic airway inflammation and remodeling, and could potentially be exploited for therapeutic benefit to asthma patients.
2022-01-26 | GSE181966 | GEO
Project description:N6-methyladenosine (m6A) is the most abundant internal mRNA nucleotide modification in mammals, regulating critical aspects of cell physiology and differentiation. The YTHDF proteins are the primary readers of m6A modifications and exert physiological functions of m6A in the cytosol. Elucidating the regulatory mechanisms of YTHDF proteins is critical to understanding m6A biology. Here, we report a mechanism that protein post-translational modifications control the biological functions of the YTHDF proteins. We find that YTHDF1 and YTHDF3, but not YTHDF2, carry high levels of nutrient-sensing O-GlcNAc modifications. O-GlcNAc modification attenuates the translation promoting function of YTHDF1 and YTHDF3 by blocking their interactions with proteins associated with mRNA translation. We further demonstrate that O-GlcNAc modifications on YTHDF1 and YTHDF2 regulate the assembly, stability, and disassembly of stress granule, facilitating rapid exchange of m6A-modified mRNAs in stress granules for recovery from stress. Therefore, our results discover an important regulatory pathway of YTHDF functions, adding an additional layer of complexity to the post-transcriptional regulation function of mRNA m6A.
2023-08-31 | GSE216570 | GEO
Project description:Innate lymphoid cells (ILCs) are able to directly respond to alarmin signals and produce an array of effector molecules for immune protection and tissue homeostasis. However, how posttranscriptional machinery in ILCs execute extracellular stimuli towards robust gene expression is yet to understand. Here, we reported a cell type-specific role of N6-methyladenosine (m6A) RNA methylation in ILCs. Inducible deletion of m6A methyltransferase METTL3 had little impact on ILC maintenance in the steady state or cytokine-induced ILC1 or ILC3 activation, but dramatically diminished IL-25-triggered ILC2 response. Specific deletion of Mettl3 in ILC2 significantly attenuated cell expansion, cytokine production, inter-organ migration, and anti-helminth immunity. To investigate the molecular mechanism by which m6A modification regulates ILC2 response, we subjected IL-25-activated iILC2 to a m6A-tagged mRNA immunoprecipitation sequencing (meRIP-seq) to identify the m6A modified mRNA.
2023-06-26 | GSE207292 | GEO
Project description:Innate lymphoid cells (ILCs) are able to directly respond to alarmin signals and produce an array of effector molecules for immune protection and tissue homeostasis. However, how posttranscriptional machinery in ILCs execute extracellular stimuli towards robust gene expression is yet to understand. Here, we reported a cell type-specific role of N6-methyladenosine (m6A) RNA methylation in ILCs. Inducible deletion of m6A methyltransferase METTL3 had little impact on ILC maintenance in the steady state or cytokine-induced ILC1 or ILC3 activation, but dramatically diminished IL-25-triggered ILC2 response. Specific deletion of Mettl3 in ILC2 significantly attenuated cell expansion, cytokine production, inter-organ migration, and anti-helminth immunity. To investigate the molecular mechanism by which m6A modification regulates ILC response, we subjected IL-1 plus IL-23-activated ILC3 to a m6A-tagged mRNA immunoprecipitation sequencing (meRIP-seq) to identify the m6A modified mRNA.
2023-06-26 | GSE223083 | GEO
Project description:Innate lymphoid cells (ILCs) are able to directly respond to alarmin signals and produce an array of effector molecules for immune protection and tissue homeostasis. However, how posttranscriptional machinery in ILCs execute extracellular stimuli towards robust gene expression is yet to understand. Here, we reported a cell type-specific role of N6-methyladenosine (m6A) RNA methylation in ILCs. Inducible deletion of m6A methyltransferase METTL3 had little impact on ILC maintenance in the steady state or cytokine-induced ILC1 or ILC3 activation, but dramatically diminished IL-25-triggered ILC2 response. Specific deletion of Mettl3 in ILC2 significantly attenuated cell expansion, cytokine production, inter-organ migration, and anti-helminth immunity. To investigate the molecular mechanism by which m6A modification regulates ILC response, we subjected IL-12 plus IL-18-activated ILC1 to a m6A-tagged mRNA immunoprecipitation sequencing (meRIP-seq) to identify the m6A modified mRNA.
2023-06-26 | GSE223081 | GEO
Project description:N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, plays important roles in many physiological and pathological processes, including the development and progression of cancer. RNA modification by m6A is regulated by methyltransferases, demethylases, and m6A-binding proteins that function in large part by regulating mRNA expression and function. Here, we investigate the expression of m6A regulatory proteins in breast cancer. We find that expression of KIAA1429/VIRMA, a component of the m6A methyltransferase complex, is upregulated in breast cancer tissue and correlates positively with poor survival. KIAA1429/VIRMA is mislocalized to the cytosol of breast cancer tissues and cell lines, and shRNA-mediated knockdown inhibits breast cancer cell proliferation, migration, and invasion. Mechanistically, KIAA1429/VIRMA is shown to bind to the m6A-dependent RNA binding protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), leading to recruitment and stabilization of m6A-modified hyaluronan synthase 2 (HAS2) mRNA. HAS2 mRNA and KIAA1429/VIRMA mRNA levels correlate positively in breast cancer tissues, suggesting that the KIAA1429/VIRMA-IGF2BP3-HAS2 axis promotes breast cancer growth and contributes to poor prognosis.
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Project description:Activin and Wnt signaling are necessary and sufficient for mesendoderm (ME) differentiation of human embryonic stem cells (hESCs). In this study, we report that during the Activin and Wnt induced ME differentiation, Activin/Smad2 induces decrease of the repressive histone modification H3K27me3 by promoting proteasome-dependent degradation of EZH2. As a result, recruitment of the forkhead protein FOXH1 on open chromatin regions integrates the signals of Activin/Smad2 and Wnt/β-catenin to activate the expression of the ME genes including HAS2 and ALDH3A2. Knockdown of HAS2 and ALDH3A2 greatly attenuates ME differentiation. These findings unveil a pathway from extracellular signals to epigenetic modification-mediated gene activation during ME commitment.
2018-09-29 | GSE113047 | GEO