The RNA demethylase FTO controls m6A marking on SARS-CoV-2 and classifies COVID-19 severity in patients
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA832334 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18932627.fastq.gz | Fastqsanger.gz | |||
| SRR18932628.fastq.gz | Fastqsanger.gz | |||
| SRR18932629.fastq.gz | Fastqsanger.gz | |||
| SRR18932630.fastq.gz | Fastqsanger.gz | |||
| SRR18932631.fastq.gz | Fastqsanger.gz |
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Project description:The RNA modification N6-methyladenosine (m6A) plays a key role in the life cycles of several RNA viruses. Whether this applies to SARS-CoV-2 and whether m6A affects the outcome of COVID-19 disease is still poorly explored. Here we report that the RNA demethylase FTO strongly affects both m6A marking of SARS-CoV-2 and COVID-19 severity. By m6A profiling of SARS-CoV-2, we confirmed in infected cultured cells and showed for the first time in vivo in hamsters that the regions encoding TRS_L and the nucleocapsid protein are multiply marked by m6A, preferentially within RRACH motifs that are specific to β-coronaviruses and well conserved across SARS-CoV-2 variants. In cells, downregulation of the m6A demethylase FTO, occurring upon SARS-CoV-2 infection, increased m6A marking of SARS-CoV-2 RNA and slightly promoted viral replication. In COVID-19 patients, a negative correlation was found between FTO expression and both SARS-CoV-2 expression and disease severity. FTO emerged as a classifier of disease severity and hence a potential stratifier of COVID-19 patients.
2023-04-26 | GSE201626 | GEO
Project description:FTO was found to inhibit keratinocyte inflammation and proliferation in both in vitro and in vivo settings, independent of m6A demethylase function. RNA-seq was used to identify fibronectin (FN1,FN) as a potential target for FTO. FTO does not rely on demethylase activity to decrease FN1 expression. The anti-inflammatory and anti-proliferative effects of FTO on psoriasis partly depend on FN1. FTO may regulate the skipping of EDA exon in FN1.
2024-05-31 | GSE253791 | GEO
Project description:Maintaining genomic integrity and faithful transmission of genetic information are essential for the survival and proliferation of cells and organisms. DNA damage, which threatens the integrity of the genome, is rapidly sensed and repaired by mechanisms collectively known as DNA damage response in cells. Using an unbiased quantitative proteomic approach, we revealed the interactome of an RNA demethylase FTO (fat mass and obesity-associated protein). We identified a direct interaction with the DNA damage sensor protein PARP1 (poly-ADP-ribose polymerase 1), which dissociates upon ultraviolet (UV) stimulation. FTO inhibits PARP1 catalytic activity and controls its clustering in the nucleolus. Loss of FTO enhances PARP1 enzymatic activity and the rate of PARP1 recruitment to DNA damage sites, thus accelerating DNA repair and, consequently, cell survival. Thus, our study establishes FTO as an endogenous negative regulator of PARP1 and the UV-induced DNA damage response, which has implications for the treatment options of various cancers.
2025-03-26 | PXD041638 | Pride
Project description:FTO, an N6-methyladenosine (m6A) demethylase, can promote cervical cancer cell proliferation and migration. RNA-sequencing of SiHa cells with FTO knockdown was conducted to dissect the differentially expressed genes and the potential mechanism of FTO in cervical cancer.
2020-02-13 | GSE133517 | GEO
Project description:Functional CD8+ T cell immune response is critical for immune surveillance and host defense against infection and tumor. Epigenetic mechanisms associated with RNA modification in controlling CD8+ T cell response remain poorly understood. Here, by T cell-specific deletion of fat mass and obesity-associated protein (FTO), a critical N6-methyladenosine (m6A) demethylase, we revealed that FTO was indispensable for sufficient CD8+ T cell immune response and protective function. FTO ablation led to considerable cell death in activated CD8+ T cells, which was attributed to apoptosis. MeRIP-seq analysis identified the upregulated m6A modification on Fas mRNA in FTO deficient CD8+ T cells. Loss of FTO promoted Fas expression via enhancing the Fas mRNA stability dependent on m6A reader IGF2BP3. Mutation of the Fas m6A sites or knockdown IGF2BP3 could rescue the upregulated Fas expression and cell apoptosis caused by FTO ablation in CD8+ T cells. Our findings defined a novel epigenetic regulatory mechanism of FTO-mediated m6A modification in supporting CD8+ T cell immune responses, providing new insights into understanding the post-transcriptional regulation in CD8+ T cell immunological functions.
2025-04-15 | GSE270717 | GEO
Project description:Reversible RNA modification of N6-methyladenosine (m6A) plays a critical role in post-transcriptional gene regulation1-13. Although the fat mass and obesity-associated protein (FTO) has been previously shown to function as an m6A demethylase in nuclear RNA1,14, its exact function in disease pathogenesis remains a mystery. Here, we demonstrate that FTO suppresses the activation of Rho GTPase signaling via both its demethylation activity and specific interaction with Rho effector, Rhotekin (RTKN)15. The knockdown of FTO activates RhoA and RhoC, induces stress fibres, and accelerates cell migration. Endogenous RTKN is highly expressed in certain cancer and cancer-derived cell lines16,17 with overexpression of RTKN leading to moderate activation of Rho18. We further found that overexpression of RTKN blocks nuclear import of FTO and traps FTO in the cytoplasm to mediate m6A demethylation of cytosolic mRNA, thereby changing gene expression by preventing m6A-dependent mRNA decay and translation. Our results illustrate how FTO represses Rho activation through m6A demethylation and direct interaction with RTKN, and shed new light on FTO-dependent post-transcriptional gene regulation in RTKN overexpressed cancers, which may provide a new direction for developing anti-cancer therapies.
2018-12-31 | GSE83540 | GEO
Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.
2024-08-26 | GSE228607 | GEO
Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.
2024-08-26 | GSE228606 | GEO
Project description:Fat mass and obesity-associated protein (FTO) can remove both the N6-methyladenosine (m6A) and N6, 2′-O-dimethyladenosine (m6Am) methylation marks that function in multiple aspects of posttranscriptional regulation. Here, we demonstrate that Zbtb48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of Zbtb48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. Zbtb48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO-dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which Zbtb48 co-ordinates RNA-binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.
2024-08-26 | GSE228605 | GEO
Project description:Despite advances in clinical diagnosis and treatment, the prognosis of patients with osteosarcoma (OS) remains poor, and the treatment efficacy has plateaued. Therefore, it is important to identify new therapeutic targets for OS. N6-methyladenosine (m6A) modification has been reported to participate in tumor malignancy. In this study, functional screening found that the m6A demethylase FTO could be a candidate therapeutic target for OS. Upregulated FTO in OS could predict a poorer prognosis. FTO promoted the growth and metastasis of OS in vitro and in vivo. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were performed to identify DACT1 as a potential target of FTO. In vitro assays demonstrated that FTO could reduce the mRNA stability of DACT1 via m6A demethylation, which decreased DACT1 expression and further activated the Wnt signaling pathway. The oncogenic effect of FTO on OS was dependent on DACT1. In addition, the m6A reader IGF2BP1 was validated to participate in the regulation of DACT1. Entacapone, a conventional drug for Parkinson's disease, was confirmed to suppress OS via m6A-mediated regulation through the FTO/DACT1 axis. Our findings demonstrate that FTO may be a novel therapeutic target and that entacapone has the preclinical value to be repurposed for OS.
2024-11-30 | GSE189878 | GEO