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The m6A methyltransferase METTL14 promotes oncogenic Kras induced juvenile myelomonocytic leukemia through dysregulating autophagy [RNA-seq]

ABSTRACT: The M6A modification plays an important role in the pathogenesis of various myeloid malignancies. However, its specific role in RAS mutant-induced myeloid malignancy is incompletely understood. In this study, we found that m6A methyltransferase METTL14 was highly expressed and associated with a shorter survival in a RAS-mutant myeloid malignancy, juvenile myelomonocytic leukemia (JMML). The knockout of METTL14 was revealed to significantly promote hematopoietic stem/progenitor cells (HSPCs) expansion and suppresses disease progression in a KrasG12D/+ mutant-induced mouse model of JMML. Moreover, knockout of METTL14 reduces hyperproliferation of KrasG12D/+ HSPCs and suppresses oncogenic KrasG12D/+-induced myeloid disease in a cell-autonomous manner. Mechanistically, we revealed that the knockout of METTL14 reduced the autophagy levels of HSPCs by suppressing the transcription and translation of autophagy-related genes, such as Atg5 and Atg9a, through m6A modification. Furthermore, we found that the autophagy inhibition through knockout of ATG5 in Kras mutant mice promoted the expansion of HSPCs and inhibited the progression of leukemia disease, consistent with the phenotypes of knockout of METTL14. Finally, we observed that combined treatment with an m6A inhibitor and a MEK inhibitor synergistically suppressed JMML growth. Collectively, these findings highlight the critical role of METTL14 in JMML tumorigenesis and suggest that m6A RNA modification represents a promising therapeutic target for this disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE298142 | GEO | 2026/01/21

REPOSITORIES: GEO

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The m6A methyltransferase METTL14 promotes oncogenic Kras induced juvenile myelomonocytic leukemia through dysregulating autophagy

Project description:The M6A modification plays an important role in the pathogenesis of various myeloid malignancies. However, its specific role in RAS mutant-induced myeloid malignancy is incompletely understood. In this study, we found that m6A methyltransferase METTL14 was highly expressed and associated with a shorter survival in a RAS-mutant myeloid malignancy, juvenile myelomonocytic leukemia (JMML). The knockout of METTL14 was revealed to significantly promote hematopoietic stem/progenitor cells (HSPCs) expansion and suppresses disease progression in a KrasG12D/+ mutant-induced mouse model of JMML. Moreover, knockout of METTL14 reduces hyperproliferation of KrasG12D/+ HSPCs and suppresses oncogenic KrasG12D/+-induced myeloid disease in a cell-autonomous manner. Mechanistically, we revealed that the knockout of METTL14 reduced the autophagy levels of HSPCs by suppressing the transcription and translation of autophagy-related genes, such as Atg5 and Atg9a, through m6A modification. Furthermore, we found that the autophagy inhibition through knockout of ATG5 in Kras mutant mice promoted the expansion of HSPCs and inhibited the progression of leukemia disease, consistent with the phenotypes of knockout of METTL14. Finally, we observed that combined treatment with an m6A inhibitor and a MEK inhibitor synergistically suppressed JMML growth. Collectively, these findings highlight the critical role of METTL14 in JMML tumorigenesis and suggest that m6A RNA modification represents a promising therapeutic target for this disease.

2026-01-21 | GSE298134 | GEO

Roles of Mettl14 in mouse limb bud development

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2025-04-03 | PXD049092 | Pride

METTL14 facilitates global genome repair and suppresses skin tumorigenesis

Project description:Global genome repair (GGR), a subpathway of nucleotide excision repair (NER), corrects bulky helix-distorting DNA lesions across the whole genome, and is essential for preventing mutagenesis and skin cancer. Here we show that METTL14 (methyltransferase-like 14), a critical component of the m6A RNA methyltransferase complex, promotes GGR through regulating m6A mRNA methylation-mediated DDB2 translation and suppresses UV-induced skin tumorigenesis. Ultraviolet B irradiation (UVB) down-regulates METTL14 protein through NBR1-dependent selective autophagy. METTL14 knockdown decreases GGR and DDB2 abundance. Conversely, overexpression of wild-type METTL14, but not its enzymatically inactive mutant, increases GGR and DDB2 abundance. METTL14 knockdown decreases m6A methylation and translation of the DDB2 transcripts. Adding DDB2 reverses the GGR repair defect in METTL14 knockdown cells, indicating that METTL14 facilitates GGR through regulating DDB2 m6A methylation and translation. Similarly, knockdown of YTHDF1, an m6A reader promoting translation of m6A modified transcripts, decreased DDB2 protein levels. Both METTL14 and YTHDF1 bind to the DDB2 transcript. In mice, skin-specific heterozygous METTL14 deletion increases UV-induced skin tumorigenesis. Furthermore, METTL14 as well as DDB2 is down-regulated in human and mouse skin tumors and by chronic UV irradiation in mouse skin, and METTL14 level is associated with the DDB2 level, suggesting a tumor-suppressive role of METTL14 in UV-associated skin tumorigenesis in association with DDB2 regulation. Taken together, these findings demonstrate that METTL14 is a target for selective autophagy and acts as a critical epitranscriptomic mechanism to regulate GGR and suppresses UVB-induced skin tumorigenesis.

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Unique position of ATG5 in the atg8ylation cascade provides a switch between autophagy and secretion

Project description:ATG5 is a part of the E3 ligase directing lipidation of ATG8 proteins (mATG8s), a process central to membrane atg8ylation and its downstream homeostatic manifestations, including canonical autophagy, with impact on health. Genetic ablation of ATG5 in myeloid cells causes mortality in murine models of tuberculosis. Paradoxically, this in vivo phenotype is specific to ATG5 and does not apply to other ATGs. Here we show that absence of ATG5 but not of other components of canonical autophagy, promotes lysosomal exocytosis, secretion of extracellular vesicles, and in neutrophils their excessive degranulation. This is due to lysosomal disrepair in ATG5 knockout cells and sequestration of ESCRT proteins by an alternative ATG conjugation complex. These findings explain the unique nature of ATG5 in host-protective role in murine experimental models of tuberculosis, and emphasize the significance of the branching aspects of the atg8ylation conjugation cascade beyond the canonical autophagy.

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N6-methyladenosine methyltransferase METTL14-mediated autophagy in malignant development of oral squamous cell carcinoma

Project description:N6-methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotes and is related to stability, localization, or translation efficiency in tumorigenesis. Autophagy plays an important role in the occurrence and development of tumours. However, the relationship between m6A and autophagy remains unclear. In this study, we used a rapamycin-induced autophagy model of oral squamous cell carcinoma (OSCC) cells, and observed increased m6A RNA methylation. When autophagy was activated, the methyltransferase-like 14 (METTL14) expression was upregulated and influenced the proliferation, migration, and invasiveness of OSCC cells. Through meRIP-seq and RNA-seq analysis, we found that METTL14 directly combined with eukaryotic translation initiation factor gamma 1 (eIF4G1) mRNA and decreased its RNA stability. According to the dual-luciferase reporter and mutagenesis assay, the mutated site 1 of exon 11 of eIF4G1 is the key target of METTL14. Knockdown of the main m6A binding protein YTHDF2 may rescue the shortened half-life of eIF4G1 mRNA induced by METTL14 overexpression. Furthermore, an in vivo tumour xenograft model confirmed that a high METTL14 expression can effectively reduce OSCC growth. Additionally, using clinical samples, we found that patients with advanced or moderately/poorly differentiated tumours exhibited lower METTL14 levels. Taken together, our results revealed that METTL14 mediated eIF4G1 expression via m6A modification and regulated autophagy levels and biological functions in OSCC. Our findings not only expand our understanding of the correlation between autophagy and RNA methylation in tumorigenesis but also present an opportunity to develop new therapeutic options.

2021-11-17 | GSE186581 | GEO

Widespread N6-methyladenosine-dependent RNA Structural Switches Regulate RNA-Protein Interactions

Project description:We show that N6-methyladenosine (m6A), the most abundant internal modification in mRNA/lncRNA with still poorly characterized function, alters RNA structure to facilitate the access of RBM for heterogeneous nuclear ribonucleoprotein C (hnRNP C). We term this mechanism m6A-switch. Through combining PAR-CLIP with Me-RIP, we identify 39,060 m6A-switches among hnRNP C binding sites transcriptome-wide. We show that m6A-methyltransferases METTL3 or METTL14 knockdown decreases hnRNP C binding at 16,582 m6A-switches. Taken together, 2,798 m6A-switches of high confidence are identified to mediate RNA-hnRNP C interactions and affect diverse biological processes including cell cycle regulation. These findings reveal the biological importance of m6A and provide insights into the sophisticated regulation of RNA-RBP interactions through m6A-induced RNA structural remodeling. Measure the m6A methylated hnRNP C binding sites transcriptome-wide by PARCLIP-MeRIP; measure the differential hnRNP C occupancies upon METTL3/METTL14 knockdown by PAR-CLIP; measure RNA abundance and splicing level changes upon HNRNPC, METTL3 and METTL14 knockdown

2015-02-27 | E-GEOD-56010 | biostudies-arrayexpress

RNA methylation destabilizes developmental regulators in murine embryonic stem cells (m6A)

Project description:m6A-seq of mouse embryonic stem cell wildtype or mutant depleted of Mettl3 or Mettl14 m6A-mRNA library for mouse embryonic stem cell each having one biological replicate were generated using HiSeq2000 v3 flowcell (Illumina) and sequenced for 100 bases with separate 7 base indexing read in a single lane.

2014-01-06 | E-GEOD-46878 | biostudies-arrayexpress

Cancer Mutations Rewire the RNA Methylation Specificity of METTL3-METTL14

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

Impact of conditional autophagy knockout on cytotoxic CD8 T cells at day 7 and day 8 after influenza infection

Project description:To investigate the role of autophagy on cytotoxic CD8 T cells, we developed a new mouse that expresses an Atg5 gene with loxP sites up- and downstream of the exon 3, Cre-recombinase, T cell receptor specific for the OVA peptide SIINFEKL and the congenic marker Thy1.1. These cells were adoptively transferred into wild type mice followed by influenza-OVA infection and induction of Atg5 knockout at day 5 after infection. Tracking the kinetic of the cells show, that the Atg5 knockout cells do not expand as much as the control cells and they experience complete contraction within few days. No memory population is established. To investigate differences in Atg5 knockout cells versus control cells we sorted the donor cells at the peak of immune response and investigated their gene expression profile via microarray analysis. 10.000 naive CD8 T cells were isolated from the spleens of transgenic mice (untreated) and were adoptively transferred into naive wild type mice. On the next day these mice got intranasally infected with 15 plaque forming units of Influenza strain A/PR8-OVA. At day 5 to 8, Atg5 knockout was induced by intraperitoneal tamoxifen administration. At day 7 and 8, donor cells were sorted from spleens, RNA was isolated and investigated via microarray. Three groups of transgenic cells were compared in two independent experiments: Atg5 knockout cells were compared to two groups of control cells: 1. heterozygously Atg5 loxP expressing cells and 2. homozygously Atg5 loxP expressing cell that lacked the expression of Cre-recombinase.

2015-04-23 | E-GEOD-49254 | biostudies-arrayexpress

METTL14 is a chromatin regulator independent of RNA N6-methyladenosine (ChIP-Seq)

Project description:METTL3 and METTL14 are two components that form the core heterodimer of the main RNA m6A methyltransferase complex (MTC, also known as m6A writer) that installs m6A. Surprisingly, depletion of METTL3 or METTL14 displayed distinct effects on mouse embryonic stem cell (mESC) self-renewal. While comparable global hypo-methylation in RNA m6A was observed in Mettl3 or Mettl14 knockout mESCs, respectively. Mettl14 knockout led to a globally decreased nascent RNA synthesis, whereas Mettl3 depletion resulted in transcription upregulation, suggesting that METTL14 might possess an m6A-indenepent role in gene regulation. We found that METTL14 colocalizes with the repressive H3K27me3 modification and PRC2 complex. Mechanically, METTL14, but not METTL3, recognizes H3K27me3 and recruits KDM6B to induce H3K27me3 demethylation independent of METTL3. Depletion of METTL14 thus led to a global increase in H3K27me3 level along with a global gene suppression . The regulation of H3K27me3 by METTL14 is essential to the transition of mESCs from self-renewal to differentiation. This work reveals a regulation mechanism on heterochromatin by METTL14 in a manner distinct from METTL3 and independently of m6A, and critically impacts transcriptional regulation, stemness maintenance and differentiation of mESCs.

2024-08-16 | GSE183397 | GEO

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