Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

METTL14-induced m6A methylation increases G6pc biosynthesis, hepatic glucose production and metabolic disorders in obesity

ABSTRACT: RNA N6-methyladenosine (m6A) modification emerges as a pivotal mechanism underpinning numerous intracellular processes. METTL14 dimerizes with METTL3 as a m6A writer to install m6A on mRNA. Subsequently, m6A readers bind to m6A-marked RNAs to influence their metabolism/fate. However, there is a knowledge gap in m6A writers and readers governing liver metabolism. Glucose-6-phosphatase catalytic subunit (G6pc) is the gatekeeper of glycogenolysis and gluconeogenesis, determining hepatic glucose production (HGP); however, posttranscriptional regulation of G6pc is poorly understood. Here, we identify METTL14 as a posttranscriptional regulator of G6pc synthesis. Deletion of Mettl14 decreased, whereas overexpression of METTL14 increased, G6pc mRNA m6A methylation in hepatocytes. We mapped five m6A sites, and mutating the 5 sites (G6pcΔ5A) blocked METTL14-induced m6A methylation of G6pcΔ5A mRNA. METTL14 increased G6pc but not G6pcΔ5A mRNA stability and translation. YTHDF1 and YTHDF3 acted as m6A readers for G6pc mRNA to increase G6pc synthesis. Deletion of Mettl14 decreased gluconeogenesis in primary hepatocytes, liver slices, and mice. Liver METTL14, METTL3, and m6A-methylated G6pc mRNA were upregulated in mice with diet-induced obesity. Deletion of hepatic Mettl14 decreased HGP and mitigated diet-induced metabolic disorders. Collectively, these results unveil a previously-unrecognized METTL14/G6pc mRNA m6A/G6pc biosynthesis/HGP axis guiding glucose metabolism in health and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE290887 | GEO | 2025/03/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Primarily Dissecting the Autonomous and Cooperative Functions of METTL3 and METTL14 in mRNA Modification and Tumor Progression

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

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

Mettl3-/Mettl14-mediated mRNA N6-methyladenosine modulates murine spermatogenesis

Project description:Spermatogenesis is precisely controlled at the transcriptional, posttranscriptional, and translational levels. Here we report that N6-methyladenosine (m6A), an epitranscriptomic mark regulating gene expression, plays essential roles during spermatogenesis. We present comprehensive m6A mRNA methylomes of mouse spermatogenic cells from five developmental stages: undifferentiated spermatogonia, type A1 spermatogonia, preleptotene spermatocytes, pachytene/diplotene spermatocytes, and round spermatids. Germ cell-specific inactiva- tion of the m6A RNA methyltransferase Mettl3 or Mettl14 with Vasa-Cre causes loss of m6A and depletion of SSCs. m6A depletion dysregulates translation of transcripts that are required for SSC proliferation/differentiation. Com- bined deletion of Mettl3 and Mettl14 in advanced germ cells with Stra8-GFPCre disrupts spermiogenesis, whereas mice with single deletion of either Mettl3 or Mettl14 in advanced germ cells show normal spermatogenesis. The sper- matids from double-mutant mice exhibit impaired translation of haploid-specific genes that are essential for spermio- genesis. This study highlights crucial roles of mRNA m6A modification in germline development, potentially ensuring coordinated translation at different stages of spermatogenesis.

2020-11-11 | GSE161059 | GEO

Increased PTCHD4 expression via m6A modification of PTCHD4 mRNA promotes senescent-cell survival [RNA-seq]

Project description:RNA modifications, including m6A, critically modulate protein expression program in a range of cellular processes. Although cellular senescence has been linked to age-related diseases and functional declines, the landscape and impact of m6A modification are poorly understood. Here, we report a robust m6A modification of Patched-Domain Containing Protein 4 (PTCHD4) mRNA at m6A in senescent cells. The METTL3/METTL14 complex was found to mediate the m6A modification of PTCHD4 mRNA, which increased PTCHD4 mRNA stability and PTCHD4 production. MeRIP RT-qPCR and eCLIP analyses were used to map this m6A modification to the last exon of PTCHD4 mRNA. Further investigation identified IGF2BP1, but not other m6A readers, as being responsible for stabilization and increased abundance of PTCHD4 mRNA by m6A modification. Silencing PTCHD4, a transmembrane protein, enhanced growth arrest and DNA damage in pre-senescent cells, and sensitized them to senolytic treatments and apoptosis. Our results support the notion that m6A modifications critically control senescence programs, and that factors such as METTL3/METTL14 and IGF2BP1, implicated in PTCHD4 mRNA m6A metabolism, could be exploited to eliminate senescent cells for therapeutic benefit.

2024-12-18 | GSE247596 | GEO

Increased PTCHD4 expression via m6A modification of PTCHD4 mRNA promotes senescent-cell survival [array]

2024-12-18 | GSE246934 | GEO

Increased PTCHD4 expression via m6A modification of PTCHD4 mRNA promotes senescent-cell survival [CLIP-seq]

2024-12-18 | GSE247595 | GEO

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

m6A independent genome-wide METTL3 and METTL14 redistribution drives senescence-associated secretory phenotype [RNA-seq]

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 | GSE141991 | GEO

m6A independent genome-wide METTL3 and METTL14 redistribution drives senescence-associated secretory phenotype [carRNA-m6A-seq]

2020-12-10 | GSE159550 | GEO