The tumor intrinsic role of the m6A reader YTHDF2 in regulating immune evasion [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA999254 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25439835_1.fastq.gz | Fastqsanger.gz | |||
| SRR25439835_2.fastq.gz | Fastqsanger.gz | |||
| SRR25439836_1.fastq.gz | Fastqsanger.gz | |||
| SRR25439836_2.fastq.gz | Fastqsanger.gz | |||
| SRR25439837_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.
2024-05-31 | GSE239426 | GEO
Project description:Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.
2024-05-31 | GSE239423 | GEO
Project description:Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.
2024-05-31 | GSE256058 | GEO
Project description:The tumor intrinsic role of the m6A reader YTHDF2 in regulating immune evasion
| PRJNA999268 | ENA
Project description:The tumor intrinsic role of the m6A reader YTHDF2 in regulating immune evasion [scRNA-seq]
| PRJNA999285 | ENA
Project description:The tumor intrinsic role of the m6A reader YTHDF2 in regulating immune evasion [bulk RNA-seq]
| PRJNA1077951 | ENA
Project description:The N6-methyladenosine (m6A) is the most abundant internal modification in almost all eukaryotic messenger RNAs, and is dynamically regulated. Therefore, identification of m6A readers is especially important in determining the cellular function of m6A. YTHDF2 has recently been characterized as the first m6A reader that regulates the cytoplasmic stability of methylated RNA. Here we show that YTHDC1 is a nuclear m6A reader and report the crystal structure of the YTH domain of YTHDC1 bound to m6A-containing RNA. We further determined the structure of another YTH domain, YTHDF1, and found that the YTH domain utilizes a conserved aromatic cage to specifically recognize the methyl group of m6A. Our structural characterizations of the YTHDC1-m6A RNA complex also shed light on the molecular basis for the preferential binding of the GG(m6A)C sequence by YTHDC1 and confirm the YTH domain as a specific m6A RNA reader. PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) was applied to human YTHDC1 protein to identify its binding sites.
2014-09-18 | E-GEOD-58352 | biostudies-arrayexpress
Project description:RNA epigenetics plays crucial roles in physiological and pathological processes. As the most abundant methylation of mRNA, 0.2-0.7% of the total adenosine, m6A is dynamically deposited co-transcriptionally by the methyltransferase complex, reversely removed by demethylases recognized and directly regulated by “reader” proteins. As the first identified m6A ‘reader’ protein, YTHDF2 recognizes and destabilizes m6A modified mRNAs by inducing mRNA decay or degradation in P-body and plays indispensable oncogenic or tumor suppressive roles in multiple malignant contexts by mediating distinct m6A modified mRNAs. Here, we report that YTHDF2 promotes the development of B cell malignancies by facilitating energy supplements and immune evasion. RNA-sequencing (RNA-seq) data reveal that a set of ATP production- and immune response-related genes are consistently and significantly dysregulated upon YTHDF2 knockdown (KD) in both B cell acute lymphoblastic leukemia (B-ALL) patient-derived xenotransplant (PDX) cells (IAH8R) and diffuse large B cell lymphoma (DLBCL) cells (SU-DHL-4). RNA immunoprecipitation sequencing (RIP-seq) of either wildtype or mutant YTHDF2 proteins identify target genes directly bind to YTHDF2 dependent on the RNA binding pockets. Methylation RIP-seq (MeRIP-seq) assays identify either m6A-moidfied genes or m5C-modified mRNAs, which is further confirmed by bisulfite-converted mRNA sequencing (BS-RNA-seq) in malignant B cells. Mechanically, we find that YTHDF2 enhances ATP synthesis by sustaining mRNA stabilities of target genes as an m5C reader protein by interacting with PABPC1, a well-know m5C-modified mRNA stabilizer. Further RNA-seq upon PABPC1 KD and RIP-seq assays for PABPC1 reveal the overlapped genes which are also regulated and bound with YTHDF2 via m5C modification. Strikingly, RNA-seq and m6A-MeRIP-seq data show that YTHDF2 promotes immune evasion by destabilizing CD19 and MHC-II molecules (e.g., HLA-DMA and HLA-DMB) in an m6A-dependent manner. Single cell RNA-seq (scRNA-seq) data further reveal the immune microenvironment and cell proportions in bone marrow of Ythdf2 conditional KO mouse models (Ythdf2fl/fl). Our proof-of-concept study discovers that a YTHDF2 selective inhibitor (e.g. CCI-38) significantly inhibits cell metabolism and immune evasion in malignant B cells (KOPN-8) by RNA-seq. Collectively, our data show that YTHDF2 promotes ATP synthesis and immune evasion and serves as a promising therapeutic target in B cell malignancies.
2024-12-16 | GSE247936 | GEO
Project description:Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human diseases such as cancer. Here we show that hypoxia regulates the ‘reader’ protein YTH domain family 2 (YTHDF2), to eventually stabilize the methylated oncogene mRNAs in inflammation-associated liver cancer. YTHDF2 silenced in human cancer cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. Hence, our findings provide a new insight into the mechanism by which hypoxia adapts m6A-mRNA editing to promote cancer.
2020-03-17 | GSE120860 | GEO
Project description:Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSCs). Here, we interrogated N6-methyladenosine (m6A) mRNA modifications in GSCs by methyl RNA-immunoprecipitation followed by sequencing (meRIP-seq) and transcriptome analysis, finding transcripts marked by m6A often upregulated. Interrogating m6A regulators, GSCs displayed preferential expression as well as in vitro and in vivo dependency of the m6A reader, YTHDF2, in contrast to normal neural stem cells (NSCs). While YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilized the oncogene transcripts, MYC and VEGFA, in GSCs in an m6A-dependent manner. We identified IGFBP3 as a downstream effector of the YTHDF2-MYC axis in GSCs and IGF1/IGF1R inhibitor, Linsitinib, as preferentially targeting YTHDF2-expressing cells, inhibiting the viability of GSCs without affecting NSCs and impairing in vivo glioblastoma growth. Thus, YTHDF2 links RNA epitranscriptomic modifications and GSC growth, laying the foundation for the YTHDF2-MYC-IGFBP3 axis as a specific and novel therapeutic target in glioblastoma.
2020-09-29 | GSE158741 | GEO