Mettl14 deficiency promotes Fam32a expression via m6A modifications to facilitate the hepatocyte G1/S transition
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ABSTRACT:
PROVIDER: PRJNA1244006 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32914425_1.fastq.gz | Fastqsanger.gz | |||
| SRR32914425_2.fastq.gz | Fastqsanger.gz | |||
| SRR32914426_1.fastq.gz | Fastqsanger.gz | |||
| SRR32914426_2.fastq.gz | Fastqsanger.gz | |||
| SRR32914427_1.fastq.gz | Fastqsanger.gz |
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Project description:Mettl14, a key component of the m6A methyltransferase complex, plays a crucial role in regulating mRNA stability and splicing. Reduced expression of Mettl14 is associated with hepatocellular carcinoma and liver regeneration, yet the molecular mechanisms by which it regulates the hepatocyte cell cycle remain unclear. Using RNA-Seq and MeRIP-Seq in liver-specific Mettl14 knockout mice, we found that Mettl14 deficiency stabilizes Fam32a mRNA through m6A modifications, resulting in increased Fam32a protein levels. Elevated Fam32a expression accelerates the G1/S transition by modulating Cdkn1a splicing, specifically downregulating its variant 2. These findings uncover a novel m6A-dependent mechanism that regulates hepatocyte cell cycle progression and highlight the previously unrecognized role of Fam32a in promoting the G1/S transition.
2025-03-31 | GSE293314 | GEO
Project description:We previously found that the downregulation of METTL14 played a crucial role in maintaining breast cancer stem-like properties. The present study aims to explore the impact of METTL14 knockdown on gene expressions and m6A modifications related to stemness in order to elucidate the underlying mechanisms.
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Project description:Phenotypic modifications of bacteria-plasmid coevolution facilitate gut colonization
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Project description:Protein arginine methylations are crucial post-translational modifications (PTMs) in eukaryotes, playing a significant regulatory role in diverse biological processes. Different forms of arginine methylations are known to co-exist within densely modified arginine-rich protein regions. However, pinpointing the precise pattern of arginine methylation and their functional implications have been challenging. In this study, we employed high-resolution mass spectrometry and in vitro enzyme reactions to uncover that the RGG/RG motifs located in the C-terminal region of METTL14 undergo both asymmetric and symmetric dimethylations (aDMA and sDMA). Specifically, PRMT5 catalyses the symmetric dimethylation of residues R425 and R445 within the extensively methylated region of METTL14, whereas PRMT1 demonstrates a broader substrate specificity. Our results indicate that mutating R425 and R445 to lysines reduces the catalytic efficiency of the METTL3:METTL14 complex, implying that sDMA modifications at these residues are important for MELL14’s function. Moreover, our findings underscore the role of sDMA modifications on METTL14 in regulating m6A-specific gene expression, including BRD4, SP1, and c-MYC, in acute myeloid leukaemia (AML) cell lines. Finally, the proliferation of AML cells is more sensitive to the combined inhibition of METTL3 and PRMT5 activity than inhibiting either alone. In summary, our study delineates the methylation landscape of the C terminal region of METTL14 and shows that sDMA modifications at residues R425 and R445 modulate the m6A deposition activity of the methyltransferase complex. These insights suggest that sDMA modifications in METTL14 could represent a promising therapeutic target for the treatment of AML.
2024-08-05 | PXD054570 |
Project description:Dynamic and distinct histone modifications facilitate human trophoblast lineage specification
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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:m6A regulates virtually every step in RNA metabolism. However, its toles in limb development remains largely unknown. To understand the roles, we created a limb bud-specific conditional knockout (cKO) mice and control heterozygous (cHet) mice of the Mettl14 gene, which encodes an essential subunit in the m6A methyltransferase complex METTL3/METTL14. We harvested limb buds from the mice on E12.5 and applied the proteins to quantitative mass spectrometry to understand how the depletion of Mettl14 affected the proteomes.
2025-04-03 | PXD049092 | Pride
Project description:METTL3 and METTL14 are considered to faithfully form the m6A writing complex in a 1:1 ratio, regulating the fate of mRNA by adding m6A modifications. However, recent studies have shown inconsistent expression and prognostic value of METTL3 and METTL14 in some tumors, suggesting that they may not be faithful in tumors. Pan-cancer analysis based on TCGA data reveals significant differences in expression, function, tumor burden correlation, and immune correlation between METTL3 and METTL14, especially in esophageal squamous cell carcinoma (ESCC). Knockdown of METTL3 significantly inhibits the cell proliferation in vitro and in vivo in ESCC EC109 cells, while the impact of METTL14 knockdown on proliferation is limited, and it cannot abolish the expression of METTL3 protein. mRNA-seq results indicate that METTL3 independently regulates the expression of 1615 genes, while only 776 genes are co-regulated by METTL3 and METTL14. Furthermore, through immunofluorescence co-localization, it is observed that METTL3 and METTL14 have certain inconsistencies in cellular localization. HPLC-MS results show that METTL3 independently binds to the Nop56p-associated pre-rRNA complex and mRNA splicing complex, separate from METTL14. Through bioinformatics and various omics studies, we have preliminarily discovered that METTL3 independently regulating tumor cell proliferation, and the participation in mRNA splicing may be a critical molecular mechanism. Our study provides an experimental basis and theoretical foundation for further understanding of the m6A writing complex and tumor therapy targeting METTL3.
2024-02-01 | PXD048886 | Pride
Project description:5-fluorouracil (5‑FU) based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. METTL14 is a core subunit of the m6A methyltransferase complex and has been reported to regulate the drug resistance of cancers. Here, we demonstrated that METTL14 is significantly downregulated in 5-FU-resistant CRC and METTL14 overexpression inhibits the proliferation and 5-FU resistance of CRC cells in vitro and in vivo. In addition, we found that MIB1 catalyzes the K63-linked ubiquitination of METTL14 and induces its degradation through the autolysosome pathway, while AURKA-mediated phosphorylation enhances METTL14 stability by inhibiting its ubiquitination. Moreover, we first discovered that METTL14 functions in 5-FU-resistant CRC cells by directly participating in the translation initiation of non-m6A-modified mRNAs independently of METTL3, rather than cooperating with METTL3 to methylate adenosine residues of targets. Further analysis indicated that METTL14 regulates the cell cycle process in 5-FU-resistant CRC cells. Collectively, our study not only identified METTL14 as a potential therapeutic target for 5-FU resistance in CRC but also revealed a novel translation-facilitating role of METTL14.
2023-12-01 | GSE219171 | GEO
Project description:5-fluorouracil (5‑FU) based chemotherapy is the first-line chemotherapy scheme for CRC, whereas acquired drug resistance poses a huge obstacle to curing CRC patients and the mechanism is still obscure. METTL14 is a core subunit of the m6A methyltransferase complex and has been reported to regulate the drug resistance of cancers. Here, we demonstrated that METTL14 is significantly downregulated in 5-FU-resistant CRC and METTL14 overexpression inhibits the proliferation and 5-FU resistance of CRC cells in vitro and in vivo. In addition, we found that MIB1 catalyzes the K63-linked ubiquitination of METTL14 and induces its degradation through the autolysosome pathway, while AURKA-mediated phosphorylation enhances METTL14 stability by inhibiting its ubiquitination. Moreover, we first discovered that METTL14 functions in 5-FU-resistant CRC cells by directly participating in the translation initiation of non-m6A-modified mRNAs independently of METTL3, rather than cooperating with METTL3 to methylate adenosine residues of targets. Further analysis indicated that METTL14 regulates the cell cycle process in 5-FU-resistant CRC cells. Collectively, our study not only identified METTL14 as a potential therapeutic target for 5-FU resistance in CRC but also revealed a novel translation-facilitating role of METTL14.
2023-12-01 | GSE219172 | GEO