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Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin [GLORI]

ABSTRACT: Interaction between the m6A methyltransferase METTL3 and METTL14 is critical for METTL3 to deposit m6A on various types of RNAs. It is still intriguing whether there is spatial control of m6A deposition on different types of RNAs. Here, through genome-wide CRISPR/Cas9 screening based on a bimolecular fluorescence complementation (BIFC) reporter, we find the H3K27ac acetylase p300 and PAK2 inhibit the interaction between METTL3 and METTL14. We further find that p300-catalyzed acetylation of METTL3 specifically occurs on H3K27ac marked chromatin. METTL3 acetylation suppresses the binding of METTL3 on H3K27ac-marked chromatin by inhibiting its interaction with METTL14. Disruptive K-to-R mutations on the three METTL3 acetylation sites promote the m6A of chromatin-associated RNAs transcribed from p300 bound enhancers and promoters marked by H3K27ac and H3K4me1-3 other than those regions marked by H3K36me3 and H3K9me3, resulting in degradation of eRNAs and paRNAs and transcription inhibition of ferroptosis-inhibition related genes. In addition, PAK2 promotes METTL3 acetylation by phosphorylating METTL3. Inhibition of PAK2 promotes the ferroptosis induced by RSL3, ML162, as well as the chemotherapy drug CDDP in a manner that depends on the acetylation of METTL3. Our study reveals a spatial-selective way to specifically regulate the deposition of m6A on enhancer and promoter RNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE272467 | GEO | 2025/03/05

REPOSITORIES: GEO

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Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin [CUT&Tag]

Project description:Interaction between the m6A methyltransferase METTL3 and METTL14 is critical for METTL3 to deposit m6A on various types of RNAs. It is still intriguing whether there is spatial control of m6A deposition on different types of RNAs. Here, through genome-wide CRISPR/Cas9 screening, we find H3K27ac acetylase p300-mediated METTL3 acetylation suppresses the binding of METTL3 on H3K27ac-marked chromatin by inhibiting its interaction with METTL14. Consistently, p300 catalyzing the acetylation of METTL3 specifically occurs on H3K27ac marked chromatin. Disruptive mutations on METTL3 acetylation sites selectively promote the m6A of chromatin-associated RNAs from p300-bound enhancers and promoters marked by H3K27ac, resulting in transcription inhibition of ferroptosis-inhibition related genes. In addition, PAK2 promotes METTL3 acetylation by phosphorylating METTL3. Inhibition of PAK2 promotes the ferroptosis in a manner that depends on the acetylation of METTL3. Our study reveals a spatial-selective way to specifically regulate the deposition of m6A on enhancer and promoter RNAs.

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Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin [CRISPR_screen]

Project description:Interaction between the m6A methyltransferase METTL3 and METTL14 is critical for METTL3 to deposit m6A on various types of RNAs. It is still intriguing whether there is spatial control of m6A deposition on different types of RNAs. Here, through genome-wide CRISPR/Cas9 screening based on a bimolecular fluorescence complementation (BIFC) reporter, we find the H3K27ac acetylase p300 and PAK2 inhibit the interaction between METTL3 and METTL14. We further find that p300-catalyzed acetylation of METTL3 specifically occurs on H3K27ac marked chromatin. METTL3 acetylation suppresses the binding of METTL3 on H3K27ac-marked chromatin by inhibiting its interaction with METTL14. Disruptive K-to-R mutations on the three METTL3 acetylation sites promote the m6A of chromatin-associated RNAs transcribed from p300 bound enhancers and promoters marked by H3K27ac and H3K4me1-3 other than those regions marked by H3K36me3 and H3K9me3, resulting in degradation of eRNAs and paRNAs and transcription inhibition of ferroptosis-inhibition related genes. In addition, PAK2 promotes METTL3 acetylation by phosphorylating METTL3. Inhibition of PAK2 promotes the ferroptosis induced by RSL3, ML162, as well as the chemotherapy drug CDDP in a manner that depends on the acetylation of METTL3. Our study reveals a spatial-selective way to specifically regulate the deposition of m6A on enhancer and promoter RNAs.

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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.

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Project description:Recent methylome studies have located N6-methyladenosine (m6A) RNA modification on thousands of mammalian transcripts. However, its functional mechanism remains unclear. In this study, we examined the role of m6A methylation in mouse embryonic stem cells. To gain an understanding of dynamic changes in cells depleted with (proposed) methyltranferases at molecular level, we examined the time-series gene expression pattern in mESC lines using microarray analysis. After 0, 4 and 8 h incubation with scramble, shRNA for Mettl3 or Mettl14, mESC cells were collected and RNAs were isolated for microarray analysis using Affymetrix Genechip Mouse Gene 2.0 ST array. After 0 h incubation with scramble, shRNA for Mettl3 or Mettl14, mESC cells were collected and RNAs were isolated for microarray analysis using Affymetrix Genechip Mouse Gene 2.0 ST array.

2014-01-06 | E-GEOD-46879 | biostudies-arrayexpress

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

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

Project description: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.

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