METTL14 regulates neuroblastoma through the m6A modification
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1022448 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26229726_1.fastq.gz | Fastqsanger.gz | |||
| SRR26229726_2.fastq.gz | Fastqsanger.gz | |||
| SRR26229727_1.fastq.gz | Fastqsanger.gz | |||
| SRR26229727_2.fastq.gz | Fastqsanger.gz | |||
| SRR26229728_1.fastq.gz | Fastqsanger.gz |
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Project description:RNA methylation is involved in the regulation of cell response and cell fate, and is closely related to the development of tumors. METTL14 is considered to be a m6A methyltransferase. Studies have found that METTL14 is associated with the occurrence and development of a variety of tumors, but the mechanism in neuroblastoma is not clear. The expression of METTL14 in high risk patients was significantly higher than that in low risk patients. Interference with METTL14 expression in SK-N-BE(2) cells significantly interfered with cell cycle and inhibited cell proliferation, migration and invasion. In neuroblastoma, METTL14 activates the PI3K/AKT signaling pathway by targeting YWHAH by upregulating m6A levels in mRNA transcripts. In all findings, it was suggested that METTL14 has a cancer-promoting function in neuroblastoma.
2024-05-10 | GSE244350 | GEO
Project description:We investigated the mechanism by which the m6A methyltransferase METTL14 functions in neuroblastoma. To explore the downstream target genes of METTL14, we performed RNA-seq analysis and found that the expression profile of the gene was significantly altered in METTL14 knockdown SK-N-BE(2) cells. We found that overexpression of METTL14 in neuroblastoma patients was a detrimental factor.
2024-04-02 | GSE244657 | GEO
Project description:N6-methyladenosine (m6A) is the most common modification to mRNA in mammalian cells linked to development and disease. m6A controls CD4+ T cell homeostasis by targeting the IL-7/STAT5/SOCS family pathway and sustains Treg suppressive function. However, the role of m6A modification in non-conventional T cell development and function remains unknown. Here we showed that m6A modification was indispensable for NKT cell homeostasis using mice with T cell-specific deletion of RNA methylation writer METTL14 (T-Mettl14-/-). Loss of METTL14-dependent m6A modification led to the upregulation of p53-mediated apoptosis in double-positive (DP) thymocytes. The decreased lifespan of DP thymocytes reduced the efficiency of distal Va-Ja rearrangement, including the invariant Va14-Ja18 TCR, and therefore led to a profound decrease in the iNKT cell population. The residual iNKT cells in T-Mettl14-/- mice exhibited increased apoptosis and impaired maturation. In addition, loss of METTL14 upregulated Cish expression, which contributed to decreased proliferative response to IL-2 and IL-15 and impaired cytokine production upon TCR stimulation in METTL14-deficient iNKT cells. Furthermore, knocking down METTL14 in mature iNKT cells diminished their cytokine production, correlated with increased Cish expression and decreased TCR signaling. Collectively, our data reveals a critical role for METTL14- dependent-m6A modification in iNKT cell development and function, highlighting the need to take this effect into consideration for targeting m6A pathway in therapeutic settings.
2022-03-01 | GSE189339 | GEO
Project description:Vascular smooth muscle cells (VSMCs) possess significant phenotypic plasticity, shifting between a contractile phenotype and a synthetic state for vascular repair/remodelling. Dysregulated VSMC transformation, marked by excessive proliferation and migration, primarily drives intimal hyperplasia. N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in gene expression regulation; however, its impact on VSMC plasticity is not fully understood. This research investigates the alterations in m6A modification and its regulatory factors during VSMC phenotypic shifts and their influence on intimal hyperplasia. We demonstrate that METTL14, crucial for m6A deposition, significantly promotes VSMC dedifferentiation. METTL14 expression, initially negligible, is elevated in synthetic VSMC cultures, post-injury neointimal VSMCs, and human restenotic arteries. Reducing Mettl14 levels in mouse primary VSMCs decreases pro- synthetic genes, suppressing their proliferation and migration. m6A-RIP-seq profiling shows key VSMC gene networks undergo altered m6A regulation in Mettl14-deficient cells. Mettl14 enhances Klf4 and Serpine1 expression through increased m6A deposition. Local Mettl14 knockdown significantly curbs neointimal formation post-arterial injury, and reducing Mettl14 in hyperplastic arteries halts further neointimal development. We found that Mettl14 is a pivotal regulator of VSMC dedifferentiation, influencing Klf4- and Serpine1- mediated phenotypic conversion. Inhibiting Mettl14 is a viable strategy for preventing restenosis and halting restenotic occlusions
2025-03-17 | GSE291560 | GEO
Project description:Vascular smooth muscle cells (VSMCs) possess significant phenotypic plasticity, shifting between a contractile phenotype and a synthetic state for vascular repair/remodelling. Dysregulated VSMC transformation, marked by excessive proliferation and migration, primarily drives intimal hyperplasia. N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, plays a critical role in gene expression regulation; however, its impact on VSMC plasticity is not fully understood. This research investigates the alterations in m6A modification and its regulatory factors during VSMC phenotypic shifts and their influence on intimal hyperplasia. We demonstrate that METTL14, crucial for m6A deposition, significantly promotes VSMC dedifferentiation. METTL14 expression, initially negligible, is elevated in synthetic VSMC cultures, post-injury neointimal VSMCs, and human restenotic arteries. Reducing Mettl14 levels in mouse primary VSMCs decreases pro- synthetic genes, suppressing their proliferation and migration. m6A-RIP-seq profiling shows key VSMC gene networks undergo altered m6A regulation in Mettl14-deficient cells. Mettl14 enhances Klf4 and Serpine1 expression through increased m6A deposition. Local Mettl14 knockdown significantly curbs neointimal formation post-arterial injury, and reducing Mettl14 in hyperplastic arteries halts further neointimal development. We found that Mettl14 is a pivotal regulator of VSMC dedifferentiation, influencing Klf4- and Serpine1- mediated phenotypic conversion. Inhibiting Mettl14 is a viable strategy for preventing restenosis and halting restenotic occlusions
2025-03-17 | GSE291558 | GEO
Project description:Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers unfolded protein response (UPR) for stress adaptation, the failure of which induces cell apoptosis and tissue/organ damage. The molecular switches underlying how the UPR selects for stress adaptation over apoptosis remain unknown. Here we discovered that accumulation of unfolded/misfolded proteins selectively induces N6-adenosine-methyltransferase-14 (METTL14) expression. METTL14 promotes CHOP mRNA decay through its 3’UTR N6-adenosine methylation (m6A) to inhibit its downstream pro-apoptotic target genes expression. UPR induces METTL14 expression through competing the HRD1-ERAD machinery to block METTL14 ubiquitination and degradation. Therefore, mice with liver-specific METTL14 deletion are highly susceptible to both acute pharmacological and alpha-1 antitrypsin (AAT) deficiency-induced ER proteotoxic stress and liver injury. Further hepatic CHOP deletion protects METTL14 knockout mice from ER stress-induced liver damage. Our study reveals a crosstalk between ER stress and mRNA m6A pathways, the ERm6A pathway, for ER stress adaptation to proteotoxicity.
2021-09-30 | GSE185109 | GEO
Project description:Methyltransferase-like 3 (METTL3) and 14 (METTL14) are core subunits of the methyltransferase complex (MTC) that catalyzes mRNA N6-methyladenosine (m6A) modification. Despite the expanding list of m6A-dependent function of the MTC, m6A independent function of the METTL3 and METTL14 complex remains poorly understood. Here we show that genome-wide redistribution of METTL3 and METTL14 drives senescence-associated secretory phenotype (SASP) in a m6A-independent manner. METTL3 and METTL14 are necessary for SASP. However, SASP is not regulated by m6A mRNA modification. METTL14 is redistributed to the enhancers, while METTL3 is localized to the pre-existing NF-B sites within the promoters of the SASP genes during senescence. METTL3 interacts with NF-B and they are mutually dependent on their associations with the promoters of SASP genes. METTL14 but not METTL3 is necessary for function of SASP gene enhancers. METTL3 and METTL14 are required for both the tumor-promoting and immune surveillance functions of senescent cells mediated by SASP in vivo in mouse models. In summary, our results report a m6A independent function of the METTL3 and METTL14 complex in promoting SASP through regulating transcription by genome-wide redistribution of METTL14 to enhancers and METTL3 to promoters of SASP genes during senescence.
2020-12-10 | GSE159550 | GEO
Project description:METTL14 forms a protein complex that induces m6A methylation on RNA but its roles in mouse limb development remains elusive. We knocked out Mettl14 in a limb bud-specific manner with the Prx1 promoter-driven Cre. The resulting Prx1-cre;Mettl14 flox/flox (conditional KO or cKO) mice showed shorter limbs with disrupted bone and cartilage development compared with the heterozygous Prx1-cre;Mettl14 wild type/flox (cHet) control mice. To understand the molecular basis for the abnormalities, we applied total RNA from day 12.5 (E12.5) embryonic limb buds to m6A-seq.
2025-04-03 | GSE271890 | GEO
Project description:Chemical modification of RNAs is important for post-transcriptional gene regulation. The METTL3-METTL14 complex generates most N6-methyladenosine (m6A) modifications in mRNAs, and dysregulated methyltransferase expression has been linked to numerous cancers. Here we show that m6A modification location, rather than the overall modification level, can impact oncogenesis. A gain-of-function missense mutation found in cancer patients, METTL14R298P, promotes malignant cell growth in culture and in transgenic mice. The mutant methyltransferase preferentially modifies noncanonical sites and transforms gene expression without increasing global m6A levels in mRNAs. The altered substrate specificity is intrinsic to METTL3-METTL14, helping us to propose a structural model for how the METTL3-METTL14 complex detects RNA sequences. Together, our work highlights that m6A location is important for function and that noncanonical methylation sites may impact aberrant gene expression and oncogenesis.
2024-12-21 | PXD039447 | Pride
Project description:To elucidate the role of METTL14-mediated m6A modification in epidermal development, we conditionally knocked out the m6A methyltransferase METTL14 in mouse epidermal keratinocytes. We then performed MeRIP-seq analysis of epidermal keratinosis from P0 control mice (K14Cre,Mettl14F/+).
2023-12-31 | GSE246652 | GEO