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RNA m6A-Ythdf1 in dendritic cells triggers anti-tumor immunity (MeRIP-Seq, RIP-Seq and Ribo-Seq in Flt3L-DCs)

ABSTRACT: Emerging evidence emphasizes the important role of tumor neoantigen in generating the spontaneous antitumor immune response and predicting the clinical response to immunotherapies. Despite the presence of numerous neoantigens, complete tumor elimination rarely occurs in majority of patients due to failures in mounting a sufficient and lasting antitumor immunity. Here we show that the durable neoanitgen-specific immunity is regulated by a m6A-binding protein, Ythdf1. In contrast to wild-type mice, Ythdf1-deficient (Ythdf1-/-) mice generate more antigen-specific CD8+ T cell response for persistent tumor control. Loss of Ythdf1 in dendritic cell (DC) results in an enhanced cross-presentation of tumor antigen and cross-priming of CD8+ T cell in vivo. To confirm our observations, we performed Ribo-Seq to analyze the translational efficiency of genes in DCs and performed m6A-seq to locate the m6A sites.

ORGANISM(S): Mus musculus

PROVIDER: GSE121933 | GEO | 2018/12/29

REPOSITORIES: GEO

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RNA m6A-Ythdf1 in dendritic cells triggers anti-tumor immunity (ribo-seq and m6a-seq in GMDCs)

Project description:Emerging evidence emphasizes the important role of tumor neoantigen in generating the spontaneous antitumor immune response and predicting the clinical response to immunotherapies. Despite the presence of numerous neoantigens, complete tumor elimination rarely occurs in majority of patients due to failures in mounting a sufficient and lasting antitumor immunity. Here we show that the durable neoanitgen-specific immunity is regulated by a m6A-binding protein, Ythdf1. In contrast to wild-type mice, Ythdf1-deficient (Ythdf1-/-) mice generate more antigen-specific CD8+ T cell response for persistent tumor control. Loss of Ythdf1 in dendritic cell (DC) results in an enhanced cross-presentation of tumor antigen and cross-priming of CD8+ T cell in vivo. To confirm our observations, we performed Ribo-Seq to analyze the translational efficiency of genes in DCs and performed m6A-seq to locate the m6A sites.

2018-12-29 | GSE115105 | GEO

RNA m6A-Ythdf1 in dendritic cells triggers anti-tumor immunity (RNA-seq and RIP-seq in in GMDCs)

Project description:Emerging evidence emphasizes the important role of tumor neoantigen in generating the spontaneous antitumor immune response and predicting the clinical response to immunotherapies. Despite the presence of numerous neoantigens, complete tumor elimination rarely occurs in majority of patients due to failures in mounting a sufficient and lasting antitumor immunity. Here we show that the durable neoanitgen-specific immunity is regulated by a m6A-binding protein, Ythdf1. In contrast to wild-type mice, Ythdf1-deficient (Ythdf1-/-) mice generate more antigen-specific CD8+ T cell response for persistent tumor control. Loss of Ythdf1 in dendritic cell (DC) results in an enhanced cross-presentation of tumor antigen and cross-priming of CD8+ T cell in vivo. To confirm our observations, we performed RNA-Seq to analyze the transcriptional level of genes in DCs and performed RNA Immunoprecipitation (RIP-seq) to locate the binding sites of Ythdf1.

2018-12-29 | GSE106772 | GEO

USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation

Project description:N6-methyladenosine (m6A) binding protein YTHDF1 is frequently upregulated in various cancers and its depletion enhances the efficacy of immune checkpoint blockade (ICB) therapy. This study reveals that USP5 interacts with YTHDF1, preventing its K11-linked polyubiquitination, thereby stabilizing YTHDF1 and promoting its oncogenic properties. In response to insulin, mTORC1 phosphorylates USP5, facilitating its dimerization and subsequent binding to YTHDF1, while the CUL7-FBXW8 complex promotes its degradation. Notably, YTHDF1 or USP5 deficiency increases PD-L1 expression and impairs immune response gene expression, contributing to immune evasion. Combining USP5 inhibitors with anti-PD-1 therapy enhances antitumor T-cell immunity and improves tumor regression in mouse models. Thus, USP5 may serve as a biomarker for stratifying patients for anti-PD-1 therapy, suggesting a novel strategy of combining USP5 inhibition with PD-(L)1 blockade to enhance cancer treatment efficacy.

2024-12-05 | GSE278264 | GEO

YTHDF1 loss in dendritic cells potentiates radiationinduced antitumor immunity via STING-dependent type I IFN production

Project description:The RNA N6-methyladenosine (m6A) reader YTHDF1 is implicated in cancer etiology and progression. We discovered that radiotherapy (RT) increased YTHDF1 expression in dendritic cells (DCs) of PBMCs from patients with cancer, but not in other immune cells tested. Elevated YTHDF1 expression in DCs was associated with poor outcomes for patients receiving RT. We found that loss of Ythdf1 in DCs enhanced the antitumor effects of ionizing radiation (IR) by increasing the cross-priming capacity of DCs across multiple murine cancer models. Mechanistically, IR upregulated YTHDF1 expression in DCs through stimulator of IFN genes/type I IFN (STING/IFN-I) signaling. YTHDF1 in turn triggered STING degradation by increasing lysosomal cathepsins, thereby reducing IFN-I production. We created a YTHDF1 deletion/inhibition prototype DC vaccine that significantly improved the therapeutic effect of RT and radioimmunotherapy in a murine melanoma model. Our findings reveal a layer of regulation between YTHDF1/m6A and STING in response to IR, which opens new paths for the development of YTHDF1-targeting therapies.

2024-10-29 | GSE272204 | GEO

YTHDF1-N6-methyladenosine-ARHGEF2 axis promoted colorectal tumorigenesis and metastasis

Project description:N6-methyladenosine (m6A) governs the fate of RNAs through m6A readers. Colorectal cancer (CRC) exhibits aberrant m6A modifications and expression of m6A regulators. However, little is known about how m6A readers interpret oncogenic m6A methylome for malignant transformation. m6A reader YTHDF1 was overexpressed by copy number gain/amplification in majority of CRCs. YTHDF1 high expression and CNVs predict increased risk of CRC relapse. Transcriptome profiles of YTHDF1-high tumors exhibit highly metastatic features. YTHDF1 promoted CRC tumor cell and organoid proliferation and enhanced metastasis. Ythdf1 knockout dampened tumor growth in carcinogen-induced CRC model. Through multiomic integration, RhoA activator ARHGEF2 was characterized as the key functional YTHDF1 target based on its m6A and YTHDF1-binding signal, translation efficiency changes, protein correlations with YTHDF1 in clinical samples, and disrupted RhoA features by YTHDF1 knockdown. Moreover, YTHDF1-ARHGEF2 co-regulation was observed in YTHDF1-overexpressing metastatic sites and carcinogen-induced Ythdf1-null CRC tumors. ARHGEF2 overexpression significantly rescued RhoA signaling, tumor cell survival and invasiveness impaired by YTHDF1 knockdown both in vitro and in vivo, further confirming the essential function of ARHGEF2.

2022-01-18 | GSE159425 | GEO

USP5 stabilizes YTHDF1 to control cancer immune surveillance through mTORC1-mediated phosphorylation

Project description:The N6-methyladenosine (m6A) binding protein YTHDF1 emerges as a frequently upregulated oncogene across various cancer types. Its depletion significantly improves the efficacy of cancer immune checkpoint blockade (ICB) treatment. A comprehensive understanding of the molecular mechanisms governing YTHDF1 protein stability is pivotal for enhancing clinical response rates and the effectiveness of ICB in cancer patients. Here, we report that USP5 interacts with YTHDF1, removing K11-linked polyubiquitination on multiple lysine residues to stabilize YTHDF1, thereby conferring its oncogenic properties. In response to insulin, mTORC1 phosphorylates USP5 at S149, promoting its dimerization. Dimerized USP5 then binds to YTHDF1, preventing its degradation. Conversely, the CUL7-FBXW8 E3 ubiquitin ligase promotes K11-linked polyubiquitination and degradation of YTHDF1. USP5 and FBXW8 thus regulate YTHDF1 ubiquitylation at defined residues through mutually exclusive interactions and opposing activities. Furthermore, deficiency in YTHDF1 or USP5 enhances PD-L1 expression and compromises the expression of multiple immune response-related genes, fostering cancer immune evasion. Remarkably, combining USP5 inhibitor treatment with anti-PD-1 immunotherapy reprograms the antitumor T-cell immunity environment, leading to enhanced tumor regression and markedly improved overall survival rates in mouse tumor models. Therefore, in hepatocellular carcinoma and lung cancer patients, USP5 may serve as a promising biomarker for stratifying individuals for anti-PD-1 therapy. Our findings reveal a ubiquitination-dependent regulation of YTHDF1 protein stability influencing immune response gene expression, suggesting USP5 inhibition combined with PD-(L)1 blockade as a novel and promising strategy for cancer treatment.

2024-12-11 | GSE255922 | GEO

mRNA-seq of neuronal compartments in shRNA-mediated knockdown of Ythdf1, -2 and -3 in mouse primary cortical neurons (mPCN)

Project description:To study the effect of m6A modifications on subcellular mRNA localization we depleted m6A readers Ythdf1, -2 and -3 with shRNAs from mouse primary cortical neurons (mPCN) and sequenced neuritic and somatic compartments in parallel with scrambled shRNA control.

2023-07-12 | E-MTAB-11569 | biostudies-arrayexpress

RNA m6A-Ythdf1 in dendritic cells triggers anti-tumor immunity

Project description:RNA m6A-Ythdf1 in dendritic cells triggers anti-tumor immunity

| PRJNA473802 | ENA

Identification of YTHDF1 targeted m6A modified transcripts in lung cancer cells

Project description:In addition to perform the m6A-seq in A549 cells, we sequenced RNA obtained from the immuno-purified complex of YTHDF1 (RIP-seq) to reveal YTHDF1 bound mRNAs, 3,676 genes were shared (m6A-seq+RIP-seq) as high-confident targets of YTHDF1 , which were mapped to cell cycle and tumor (including lung cancer) related signaling pathways in the KEGG pathway database

2019-09-26 | GSE136433 | GEO

Mettl3-m6A-YTHDF1 axis promotion of mitochondrial dysfunction in metabolic dysfunction–associated steatotic liver disease (MASLD)

Project description:The N6-methyladenosine (m6A) mRNA modification and the mitochondrial respiratory chain (MRC) hold paramount importance in the advancement of MASLD. This study thoroughly investigates the relationship and impact of m6A mRNA modification and mitochondrial function in the progression of MASLD. Here we report that the mRNA and protein levels of mitochondrial respiratory chain (MRC) subunits showed inconsistent trends in vivo experiments. Abnormal m6A modification and mitochondrial dysfunction in MASLD were attributed to the upregulation of methyltransferase like 3 (Mettl3) and the downregulation of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) induced by high-fat foods. Mettl3 promoted the MRC's function. However, knockout of the reader protein YTHDF1, which plays a crucial role in the m6A modification process, counteracted the effect of Mettl3 and suppressed MRC. In MASLD, damage to the MRC may be regulated by the Mettl3-m6A-YTHDF1 complex axis, especially by the role of YTHDF1. Our research has offered a novel perspective on the involvement of m6A mRNA methylation in the pathogenesis of MASLD.

2024-09-20 | PXD047819 | Pride

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