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YTHDF2 iCLIP in glioblastoma stem cells

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE158020 | GEO | 2020/09/29

REPOSITORIES: GEO

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The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells [RNA-seq]

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 | GSE158740 | GEO

The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells [m6A RIP-seq]

2020-09-29 | GSE158741 | GEO

Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer

Project description:We found in this study through targeted CRISPR-Cas9 screening of RBPs that disrupting YTHDF2-dependent degradation of its target transcripts triggers apoptosis of MYC-dependent cancer cells and tumors. Enhanced CLIP (eCLIP), m6A-sequencing (m6A-seq) and YTHDF2 knockdown followed by RNA-seq analysis of YTHDF2-m6A-mRNA interactions revealed extensive associations with mRNAs encoding MAPK pathway genes that when stabilized, induce epithelial-to-mesenchymal transition and stress-induced apoptosis. scRibo-STAMP profiling of translating mRNAs revealed global alterations in the translatome of single cells in YTHDF2-depleted solid tumors. Thus, our work highlights the therapeutic relevance of RBPs by uncovering the critical role of YTHDF2 in counteracting the global increase of mRNA synthesis in MYC-driven cancers.

2021-07-02 | GSE137258 | GEO

The RNA m6A reader YTHDF2 controls NK cell anti-tumor and anti-viral immunity

Project description:N6-methyladenosine (m6A) is the most prevalent post-transcriptional modification on RNA. NK cells are the predominant innate lymphoid cells that mediate anti-viral and anti-tumor immunity. However, whether and how m6A modifications affect NK cell immunity remains unknown. Here, we discover that YTHDF2, a well-known m6A reader, is upregulated in NK cells upon activation by cytokines, tumors, and cytomegalovirus infection. Ythdf2 deficiency in NK cells impairs NK cell anti-tumor and anti-viral activity in vivo. YTHDF2 maintains NK cell homeostasis and terminal maturation, correlating with modulating NK cell trafficking and regulating Eomes, respectively. YTHDF2 promotes NK cell effector function and is required for IL-15-mediated NK cell survival and proliferation by forming a STAT5-YTHDF2 positive feedback loop. Transcriptome-wide screening identifies Tardbp to be involved in cell proliferation or survival as a YTHDF2-binding target in NK cells. Collectively, we elucidate the biological roles of m6A modifications in NK cells and highlight a new direction to harness NK cell anti-tumor immunity.

2021-05-08 | GSE174027 | GEO

Cell cycle-dependent YTHDF2 promotes mitotic entry by repressing WEE1

Project description:The m6A modification regulates mRNA stability and translation. Here we show that transcriptomic m6A modification is dynamic and the m6A reader protein YTHDF2 promotes mRNA decay during the cell cycle. Depletion of YTHDF2 leads to the delay of mitotic entry due to overaccumulation of WEE1, a negative regulator of CDK1. We demonstrate that WEE1 transcripts contain m6A modification, which promotes their decay through the m6A reader YTHDF2. Moreover, we found that YTHDF2 protein stability is dependent on CDK1 activity. Thus, CDK1, YTHDF2, and WEE1 form a feedforward regulatory loop to promote mitotic entry. We further identified CUL1, CUL4A, DDB1, and SKP2 as components of E3 ubiquitin ligase complexes that mediate YTHDF2 proteolysis. Our study provides insights into how cell cycle mediators modulate transcriptomic m6A modification, which in turn regulates the cell cycle.

2020-01-01 | GSE134700 | GEO

YTHDF2 mediates the mRNA degradation in prostate cancer in m6A-dependent way

Project description:As the crucial m6A reader, YTHDF2 usually degrades the target mRNAs by recognizing the m6A modified sites, consequently altering m6A levels of each mRNA. In this study, we used m6A MeRIP sequencing to detect the m6A modification alterations in prostate cancer (PCa) cell line after knocking down YTHDF2 and identify how YTHDF2 promote the PCa progression by mediating the mRNA degradation in m6A-dependent way.

2020-11-09 | GSE129408 | GEO

SLAM-Seq analysis of Ythdf2-deficient pre-leukemic cells

Project description:The mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human acute myeloid leukemias (AML). To study the role of YTHDF2 on mRNA decay rates in leukemia, c-Kit+ cells from foetal livers of Ythdf2fl/fl; Vav-iCre (Ythdf2CKO) and Ythdf2fl/fl (Ythdf2CTL) 14.5 dpc embryos were transduced with Meis1 and Hoxa9 oncogenes and serially re-plated to generate pre-leukemic cells. Medium with 4SU was used for pre-leukemic cells labelling for 12 hours and was later replaced with 4SU-free medium (time 0). Cells were collected immediately after medium change and at 1, 3 and 9 hours for library generation. RNA from Ythdf2CKO (n=3 biological replicates) and Ythdf2CTL (n=3 biological replicates) pre-leukemic cells were used for SLAM-seq library generation.

2019-04-05 | E-MTAB-7784 | biostudies-arrayexpress

Ythdf2-mediated m6A mRNA clearance modulates neural development in mice

Project description:We found that the proliferation and differentiation capabilities of NSPCs decrease significantly in Ythdf2 null mutants.To explore the underlying molecular mechanism, we performed transcriptomics and well-established m6A-methylome analyses of NSPCs dervied from wild type and Ythdf2-/- embryo brains. RNA-seq data revealed that expressions of genes enriched in neural development pathways were significantly disturbed. The inhibitory genes, like Flrt2, Ptprd, et al. in regulation of JAK-STAT cascade, which contributes to the neuroprotection and neurite outgrowth, showed increased gene expressions and m6A enrichment by m6A-seq. We identified that without the recognizing and binding of Ythdf2, the degradation of neuron differentiation related m6A-modified mRNAs were delayed in Ythdf2-/-, thereby disturbing the proliferation and differentiation of NSPCs. In summary, our findings uncovered that Ythdf2 modulates neural developmental via regulating the clearance of mRNA targets.

2018-01-01 | GSE104867 | GEO

Expression data from YTHDF1 or YTHDF2 down-regulated PC9

Project description:The human YTH domain family protein (YTHDF) family is RNA binding protein which specifically recognizes N6-methyladenosine (m6A), and exerts distinct roles in eukaryocytes; YTHDF1 promotes the translation of m6A modified mRNAs collaborating with initiation factors, and YTHDF2 reduces the stability of the m6A-modified transcripts. We used the Nanostring nCounter to detail the differential gene expression by YTHDF1 and YTHDF2.

2021-08-24 | GSE171634 | GEO

YTHDF2 promotes DNA damage repair by positively regulating the histone methyltransferase SETDB1 in spermatogonia

Project description:we reported that in the absence of YTHDF2, spermatogonia showed significantly enhanced sensitivity to etoposide and promoted apoptosis, demonstrating that the importance of YTHDF2 in the etoposide-responsive DNA damage response (DDR). Multiple modifications involved in the DDR, some of which recruit repair factors to the sites of DNA damage. N6-methyladenosine (m6A) as a crucial component of the DNA damage repair system responding to DNA lesions. Meanwhile, H3K9me3 has been implicated in DDR, which provides site for DDR factors binding to DNA lesion. Importantly, ablation of Ythdf2 reduced SETDB1 and H3K9me3 levels, and SETDB1 overexpression qualitatively suppressed the DNA damage associated with YTHDF2 loss.

2023-12-30 | GSE217071 | GEO

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