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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

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

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

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

| PRJNA473802 | ENA

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

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

YTHDF1 Amplifies Wnt/β-Catenin Signaling to Promote Intestinal Stemness

Project description:Wnt/β-catenin signaling is essential for intestinal stem cell homeostasis and aberrant activation of this signaling leads to tumorigenesis. Here we report a function of YTHDF1, an mRNA m6A reader, in mediating β-catenin hyperactivation. Wnt signaling promotes YTHDF1 expression at the translational level. YTHDF1 is dispensable for normal intestinal development in mice while essential for intestinal regeneration. Ythdf1 knockout reduces the stemness of intestinal stem cells, which blocks Wnt-driven tumorigenesis. Genome-wide analysis identifies a subset of Wnt signaling components regulated by YTHDF1 in an m6A-dependent manner. Moreover, we demonstrate that YTHDF1 promotes the translation of TCF7L2/TCF4 to augment β-catenin activation. Targeting YTHDF1 in the established tumors leads to tumor shrinkage and prolonged survival. Together, our studies uncover YTHDF1 as an integral regulator of Wnt signaling at the translational level during intestinal tumorigenesis, which might serve as a promising target for colorectal cancer therapy.

2019-08-31 | GSE136664 | GEO

m6A-facilitated hippocampal learning and memory through Ythdf1

Project description:N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammalian messenger RNAs (mRNAs). While m6A has been shown to mark groups of mRNAs for coordinated degradation in various physiological processes, the relevance of m6A in affecting translation remains to be determined in intact biological systems in vivo. Here we show that, through its reader protein Ythdf1, m6A promotes a pulse of protein synthesis of target transcripts in response to neuronal stimuli in the adult mouse hippocampus, thereby facilitating learning and memory processes. Mice with genetic deletion of the Ythdf1 gene (Ythdf1-/-) exhibit learning and memory defects, as well as impaired hippocampal synaptic transmission and long-term potentiation (LTP). Selective re-expression of Ythdf1 in the hippocampus of adult Ythdf1-/- mice fully rescues the behavioral and synaptic defects, while hippocampus-specific knockdown of Ythdf1 or Mettl3, the catalytic component of m6A methyltransferase complex, recapitulates the hippocampal deficiency in adult mice. At the molecular level, transcriptome-wide mapping of m6A sites and RNA binding sites of Ythdf1 on hippocampal mRNAs using crosslinking immunoprecipitation followed by high-throughput sequencing (CLIP-seq) uncovered key neuronal genes, including those involved in synaptic transmission and long-term potentiation. Nascent protein labelling and tether reporter assays in cultured hippocampal neurons revealed that Ythdf1 is critical for initiating a pulse of protein synthesis of target transcripts in a neuronal-stimulus-dependent manner. Collectively, our results uncover a pathway of mRNA m6A methylation in learning and memory, which is mediated through Ythdf1 in response to stimuli.

2018-08-17 | GSE106607 | GEO

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