Affinage

METTL3

N(6)-adenosine-methyltransferase catalytic subunit METTL3 · UniProt Q86U44

Length
580 aa
Mass
64.5 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

METTL3 is the dominant catalytic subunit of the cellular N6-methyladenosine (m6A) methyltransferase machinery, accounting for the great majority of m6A on mRNA as established by exon 4 deletion combined with LC-MS/MS quantification, which also revealed that apparent METTL3-independent m6A traces to catalytically active splice isoforms (PMID:35853000). Acting with METTL14 and WTAP, METTL3 deposits m6A whose functional outcome is determined by the reader engaged: transcript stabilization through IGF2BP2 (e.g., Tcf7, TAB3, TIMP2, BATF, MIS12) (PMID:33637761, PMID:35417191, PMID:34995800, PMID:38902548, PMID:33035345), transcript destabilization through YTHDF2 (e.g., SNAP29, SIRT1, LATS1, SLC7A11) (PMID:40340690, PMID:37353804, PMID:36609396, PMID:40588140), and translational enhancement through YTHDF1 or YTHDC1-dependent processing (PMID:31015515, PMID:36399511). Through these mRNA-fate programs METTL3 controls cell-type-specific transcripts to regulate immune cell activation and inflammation (PMID:31015515, PMID:36920907, PMID:37355989), skeletal muscle hypertrophy via repression of ACVR2A and the activin/myostatin axis (PMID:35013323), cerebellar, neural, and pancreatic-lineage development (PMID:29879109, PMID:33972392, PMID:37963393), epithelial morphogenesis by tuning histone-modifier mRNAs (PMID:37656787), autophagy, ferroptosis and cellular senescence (PMID:30870073, PMID:34706873, PMID:37353804), and genome stability — promoting R-loop resolution at DNA breaks through an ARID1A–METTL3/METTL14–RNase H1 axis (PMID:38358891) and conversely supporting telomere maintenance in ALT cancer cells by m6A-marking TERRA for YTHDC1 stabilization and hnRNPA2B1-driven R-loop formation (PMID:36399511, PMID:38180812). Notably, METTL3 also acts independently of its catalytic activity, associating with ribosomes and the translation initiation machinery to promote translation of bound mRNAs, since catalytically inactive METTL3 retains this activity when tethered (PMID:27117702). METTL3 activity is tightly controlled post-translationally: SUMOylation by SUMO1 (reversed by SENP1) represses methyltransferase activity (PMID:29506078), TRIP12-mediated K48 polyubiquitination drives its degradation (PMID:38902548), lactylation of its zinc-finger domain is required for target RNA capture (PMID:35320754), and p300-mediated acetylation — promoted by PAK2 phosphorylation — blocks METTL3–METTL14 interaction to selectively limit m6A on chromatin-associated enhancer/promoter RNAs (PMID:40101711).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2016 High

    Established that METTL3 has a methyltransferase-independent function, acting directly in translation rather than solely as an m6A writer.

    Evidence Ribosome association assays and tethering of wild-type versus catalytically dead METTL3 to reporter mRNAs in cell lines

    PMID:27117702

    Open questions at the time
    • Did not define which initiation factors are essential
    • Did not establish how this catalysis-independent role is partitioned from the writer complex in vivo
  2. 2018 High

    Resolved how METTL3 activity is dampened post-translationally, showing SUMOylation represses catalytic output without altering complex assembly or stability.

    Evidence Site-directed 4KR mutagenesis, in vivo SUMOylation assay, SENP1 reversal, and m6A quantification with METTL14/WTAP co-IP

    PMID:29506078

    Open questions at the time
    • Did not identify the SUMO E3 ligase
    • Mechanism by which SUMO blocks catalysis on the assembled complex unresolved
  3. 2018 High

    Demonstrated in vivo that METTL3-deposited m6A controls mRNA stability and splicing to drive a defined developmental program (cerebellar granule cell survival).

    Evidence Nervous-system conditional Mettl3 knockout mouse with transcriptome-wide m6A mapping, RNA half-life and splicing analysis

    PMID:29879109

    Open questions at the time
    • Specific reader proteins mediating the stability/splicing effects not pinpointed
    • Direct causative target transcripts in granule cells not isolated
  4. 2019 High

    Showed that m6A outcome is reader- and target-specific, including translational enhancement of immune effectors and autophagy regulation through distinct readers.

    Evidence DC-specific Mettl3 KO with RIP and translation reporters (CD40/CD80/Tirap); m6A-RIP and HNRNPD pulldown on TFEB

    PMID:30870073 PMID:31015515

    Open questions at the time
    • How a single writer selects opposing stabilizing versus destabilizing reader outcomes per target is unresolved
    • TFEB feedback loop kinetics not fully characterized
  5. 2021 Medium

    Mapped how METTL3 tunes lineage-specifying and signaling transcripts across diverse tissues via stabilization or destabilization of distinct targets.

    Evidence Cell-type-specific KOs and morpholino knockdown with miCLIP/m6A mapping, decay assays, and genetic rescue (Tcf7 in TFH; WNT in Xenopus neural patterning; SNAP29/ATG7 in autophagy)

    PMID:33637761 PMID:33972392 PMID:34706873 PMID:40340690

    Open questions at the time
    • Cross-tissue rules governing target selection remain undefined
    • Some autophagy targets supported by single-lab studies
  6. 2022 High

    Rigorously quantified METTL3's contribution to the m6A epitranscriptome, attributing >95% of mRNA m6A to METTL3 and explaining prior discrepancies via active splice isoforms.

    Evidence CRISPR/Cas9 exon 4 deletion, splice-isoform functional assays, and LC-MS/MS m6A quantification

    PMID:35853000

    Open questions at the time
    • Did not address the residual <5% writer activity
    • Tissue-specific isoform contributions not surveyed
  7. 2022 High

    Extended METTL3 function to non-coding RNA and genome integrity, identifying TERRA m6A and YTHDC1-dependent stabilization as required for telomere maintenance in ALT cells.

    Evidence MeRIP, YTHDC1 RIP, DRIP R-loop detection, and telomere length assays in ALT cancer cells

    PMID:36399511

    Open questions at the time
    • How TERRA m6A is selectively deposited versus mRNA targets is unknown
    • Reader handoff between YTHDC1 and downstream R-loop machinery not detailed at this stage
  8. 2022 High

    Identified lactate metabolism as an upstream regulator of METTL3, both transcriptionally (H3K18 lactylation at the promoter) and post-translationally via zinc-finger lactylation required for RNA capture.

    Evidence MeRIP-seq, mass spectrometry of lactylation sites, zinc-finger mutagenesis, and myeloid-specific Mettl3 KO with JAK1/STAT3 readouts

    PMID:35320754

    Open questions at the time
    • The lactyltransferase/delactylase for the zinc-finger sites not fully defined
    • Quantitative impact of lactylation on bulk m6A unresolved
  9. 2024 High

    Defined METTL3's direct role in DNA double-strand break repair as part of an ordered ARID1A-recruited complex that methylates R-loop RNA to enable RNase H1 resolution and end resection.

    Evidence Reciprocal co-IP, ChIP, in vitro R-loop binding, MeRIP, RNase H1 recruitment and DNA end-resection/comet assays with ARID1A/METTL3/METTL14 depletion

    PMID:38358891

    Open questions at the time
    • Whether m6A on R-loop RNA is read by a specific reader to recruit RNase H1 not established
    • Relationship to the telomeric TERRA R-loop pathway not reconciled
  10. 2024 High

    Resolved how METTL3 protein abundance and chromatin engagement are controlled, identifying TRIP12-mediated K48 degradation and a PAK2→p300 acetylation switch that restricts chromatin-associated m6A.

    Evidence K48-linkage ubiquitination assays, genome-wide CRISPR screen, in vitro acetylation and PAK2 kinase assays, acetylation-site mutagenesis with ChIP-seq/m6A-seq

    PMID:38902548 PMID:40101711

    Open questions at the time
    • Interplay among SUMOylation, ubiquitination, lactylation and acetylation in a single cell not integrated
    • Deacetylase/deubiquitinase counterparts not all identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how a single writer complex achieves target- and reader-specific outcomes (stabilization vs decay vs translation) and how the network of competing post-translational modifications is coordinated to direct METTL3 to specific RNA classes in a given cell state.
  • No unifying code linking site selection to reader recruitment
  • PTM cross-talk hierarchy not reconstituted
  • Structural basis for chromatin vs cytoplasmic targeting undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0003723 RNA binding 3 GO:0016740 transferase activity 3 GO:0045182 translation regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005840 ribosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-9612973 Autophagy 3 R-HSA-73894 DNA Repair 2
Partners
ARID1AMETTL14P300PAK2SENP1TRAF6TRIP12WTAP
Complex memberships
m6A methyltransferase writer complex (METTL3-METTL14-WTAP)

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 METTL3 associates with ribosomes in the cytoplasm and promotes translation of specific mRNAs (e.g., EGFR, TAZ) through interaction with the translation initiation machinery. Both wild-type and catalytically inactive METTL3 promote translation when tethered to a reporter mRNA, indicating a methyltransferase-independent translational role. Ribosome association assay, tethering reporter assay, loss- and gain-of-function studies, co-immunoprecipitation with translation initiation factors Molecular cell High 27117702
2018 METTL3 is SUMOylated at lysine residues K177, K211, K212, and K215 by SUMO1; this modification is reversed by SENP1. SUMOylation does not alter METTL3 stability, localization, or interaction with METTL14 and WTAP, but significantly represses its m6A methyltransferase activity, reducing m6A levels in mRNAs. Site-directed mutagenesis (4KR mutant), in vivo SUMOylation assay, m6A quantification, co-immunoprecipitation with METTL14/WTAP, colony formation assay Nucleic acids research High 29506078
2018 Conditional knockout of Mettl3 in mouse nervous system causes cerebellar hypoplasia due to enhanced apoptosis of cerebellar granule cells; METTL3 depletion leads to extended RNA half-lives and aberrant splicing events, demonstrating that METTL3-mediated m6A regulates mRNA stability and splicing in cerebellar development. Conditional knockout mouse (cKO), transcriptome-wide m6A mapping, RNA half-life measurement, splicing analysis, histology PLoS biology High 29879109
2019 Mettl3-mediated m6A modification of CD40, CD80, and TLR4 signaling adaptor Tirap mRNAs enhances their translation in dendritic cells, promoting DC maturation, NF-κB signaling, and IL-12 cytokine production. DC-specific Mettl3 conditional knockout, RNA immunoprecipitation, translation reporter assay, co-stimulatory molecule expression analysis Nature communications High 31015515
2019 METTL3 methylates TFEB mRNA at two m6A residues in the 3'-UTR, promoting association of HNRNPD with TFEB pre-mRNA and decreasing TFEB expression levels, thereby negatively regulating autophagy. TFEB in turn inhibits METTL3 mRNA stability (post-transcriptionally) and induces ALKBH5, establishing a negative feedback loop. m6A-RIP, RNA immunoprecipitation (RIP), siRNA knockdown, overexpression, autophagic flux assay, GST pull-down Autophagy Medium 30870073
2022 Lactate in the tumor microenvironment induces METTL3 upregulation via H3K18 lactylation at the METTL3 promoter. METTL3 is also directly lactylated at two sites in its zinc-finger domain, which is required for target RNA capture. METTL3-mediated m6A on Jak1 mRNA is recognized by YTHDF1, enhancing JAK1 protein translation and STAT3 phosphorylation in tumor-infiltrating myeloid cells. MeRIP-seq, RIP, mass spectrometry identification of lactylation sites, site-directed mutagenesis of zinc-finger domain, JAK1 translation reporter, phospho-STAT3 western blot, myeloid-specific Mettl3 KO mice Molecular cell High 35320754
2022 METTL3 catalyzes m6A modification on TERRA (telomeric repeat-containing RNA); the m6A-modified TERRA is recognized and stabilized by the reader YTHDC1. Loss of METTL3 or YTHDC1 enhances TERRA degradation, reduces R-loop formation at telomeres, and leads to telomere shortening and instability in ALT cancer cells. MeRIP, YTHDC1 RIP, R-loop detection (DRIP), METTL3 knockdown/knockout, telomere length assay, TERRA stability assay Nucleic acids research High 36399511
2022 METTL3-mediated m6A modification of TAB3 mRNA at stop codon regions increases TAB3 mRNA stability through binding of the reader IGF2BP2, leading to NF-κB-dependent renal inflammation. Genetic and pharmacological (Cpd-564) METTL3 inhibition attenuates renal injury. MeRIP-seq, RNA-seq, RIP-qPCR, conditional Mettl3 KO mice, AAV9-mediated silencing, pharmacological inhibitor Science translational medicine High 35417191
2021 METTL3-mediated m6A modification of the Tcf7 3'-UTR stabilizes Tcf7 mRNA in T follicular helper cells; loss of METTL3 or mutation of the Tcf7 m6A site accelerates Tcf7 transcript decay and impairs TFH differentiation. Ectopic TCF-1 expression rescues TFH defects caused by METTL3 deficiency. CD4+ T cell-specific Mettl3 conditional KO, m6A-miCLIP-seq, RNA decay assay, site-directed m6A site mutation, rescue experiment with TCF-1 overexpression Nature communications High 33637761
2020 METTL3 reduces m6A modification on MIS12 mRNA in human mesenchymal stem cells; loss of m6A accelerates MIS12 mRNA turnover, reducing MIS12 expression and promoting cellular senescence. The m6A reader IGF2BP2 recognizes and stabilizes m6A-modified MIS12 mRNA. m6A transcriptional profiling, METTL3 KO/overexpression in hMSCs, RNA stability assay, IGF2BP2 RIP, senescence assays (SA-β-gal, p21) Nucleic acids research Medium 33035345
2021 METTL3 depletion decreases m6A levels in SARS-CoV-2 RNA; m6A reduction in viral RNA increases RIG-I binding and enhances downstream innate immune signaling and inflammatory gene expression, revealing that METTL3-deposited m6A on viral RNA dampens innate immune sensing. m6A-seq of SARS-CoV-2 genome, METTL3 siRNA depletion, RIG-I RIP, innate immune gene expression analysis Cell reports Medium 33961823
2022 METTL3 is responsible for >95% of m6A in mRNA as demonstrated by exon 4 deletion of Mettl3; apparent METTL3-independent m6A in prior studies was due to expression of alternatively spliced METTL3 isoforms that bypass CRISPR/Cas9 mutations and retain methyltransferase activity. CRISPR/Cas9 exon 4 deletion, alternative splicing analysis, m6A quantification by LC-MS/MS, functional activity assay of splice isoforms PLoS biology High 35853000
2022 METTL3 promotes skeletal muscle hypertrophy by repressing m6A-dependent synthesis of activin type 2A receptor (ACVR2A), blunting anti-hypertrophic myostatin signaling. Myofiber-specific conditional Mettl3 deletion causes spontaneous muscle wasting; exogenous METTL3 delivery induces muscle growth even without external triggers. Myofiber-specific conditional Mettl3 KO mice, overload-induced hypertrophy model, m6A-seq of muscle, AAV-mediated METTL3 delivery, myostatin inhibitor co-administration rescue Nature communications High 35013323
2021 METTL3-mediated m6A modification of ATG7 mRNA attenuates ATG7 RNA stability, impairing autophagosome formation and promoting cellular senescence via the GATA4 axis in fibroblast-like synoviocytes. m6A-methylated RNA immunoprecipitation, RNA immunoprecipitation, siRNA knockdown, autophagic flux assay, intra-articular AAV9-siMETTL3 injection in DMM mouse model Annals of the rheumatic diseases Medium 34706873
2024 ARID1A recognizes R-loops in an ATM-dependent manner and recruits METTL3 and METTL14 to R-loop RNA, leading to m6A methylation of R-loop RNA. This m6A modification facilitates recruitment of RNase H1 to drive R-loop resolution and promote DNA end resection at double-strand breaks, ensuring genome stability. Co-immunoprecipitation, ChIP, in vitro R-loop binding assay, MeRIP, RNase H1 recruitment assay, DNA end resection assay, METTL3/METTL14/ARID1A depletion with comet assay and cell survival Cell reports High 38358891
2024 Lactate promotes p300-mediated H3K18 lactylation at the METTL3 promoter, increasing METTL3 expression. METTL3-mediated m6A modification is enriched in ACSL4 mRNA and its stability is regulated through a YTHDC1-dependent pathway, promoting ferroptosis in alveolar epithelial cells during sepsis-associated lung injury. H3K18la ChIP at METTL3 promoter, MeRIP for ACSL4, YTHDC1 RIP, METTL3 knockdown/inhibitor in ALI mouse model Redox biology Medium 38852200
2024 TRIP12, a HECT-domain E3 ubiquitin ligase, acts as a negative regulator of METTL3 protein expression by facilitating K48-linked polyubiquitination of METTL3 in inflammatory microglia; METTL3 protein is upregulated in TBI not through transcription but through reduced proteasomal degradation. METTL3 stabilizes BATF mRNA in an m6A-IGF2BP2-dependent manner to drive neuroinflammation. Co-immunoprecipitation, ubiquitination assay (K48-linkage specific), MeRIP-seq, CUT&Tag, IGF2BP2 RIP, selective microglial Mettl3 ablation in TBI mouse model Cell death and differentiation High 38902548
2025 p300-mediated acetylation of METTL3 (occurring specifically on H3K27ac-marked chromatin) suppresses METTL3 binding to chromatin by inhibiting its interaction with METTL14, selectively reducing m6A deposition on enhancer and promoter RNAs. PAK2 promotes METTL3 acetylation by phosphorylating METTL3. Mutations at METTL3 acetylation sites selectively promote m6A on H3K27ac-marked chromatin-associated RNAs and repress ferroptosis-inhibition-related genes. Genome-wide CRISPR-Cas9 screen, in vitro acetylation assay, Co-IP (METTL3-METTL14 interaction), acetylation site mutagenesis, ChIP-seq, m6A-seq, PAK2 kinase assay Molecular cell High 40101711
2022 METTL3 controls translational upregulation of splicing factor proteins via m6A modification-mediated ribosome recycling and decoding, leading to widespread splicing dysregulation and contributing to CLL progression in a methyltransferase-dependent manner. Integrative transcriptomic and proteomic analysis, METTL3 KD in CLL cells in vitro and in vivo, ribosome profiling, m6A-seq Blood cancer discovery Medium 37067905
2023 METTL3-mediated m6A modification of TLR4 mRNA increases TLR4 translation and simultaneously slows its degradation, elevating TLR4 protein levels in neutrophils; this promotes TLR4/MyD88/NF-κB signaling activation and controls CXCR2-dependent neutrophil release from bone marrow. Neutrophil-specific Mettl3 KO mice, MeRIP-qPCR, TLR4 protein/mRNA stability assay, translation efficiency measurement, flow cytometry, LPS-induced endotoxemia model Cell reports High 36920907
2023 Mettl3 promotes m6A-mediated degradation of mRNAs encoding critical histone-modifying enzymes in epidermal progenitors; depletion of Mettl3 increases expression of these chromatin modifiers and their associated histone modifications, causing widespread gene expression abnormalities and impaired epithelial development including loss of hair follicle morphogenesis. Epidermal progenitor-specific Mettl3 KO mice, m6A-seq, histone modification profiling, transcriptome analysis, RNA stability Science advances High 37656787
2023 METTL3-mediated m6A methylation in γδ T cells prevents formation of endogenous double-stranded RNAs and promotes degradation of Stat1 transcripts; both mechanisms converge to prevent over-activation of STAT1 signaling and maintain γδ T17 cell identity. Mettl3 KO in γδ T cells, dsRNA detection assay, Stat1 mRNA decay assay, IL-17 production measurement, psoriasis mouse model Cell reports Medium 37355989
2021 METTL3 promotes m6A modification of TRAF6 mRNA 3'-UTR in microglia, and METTL3 physically interacts with TRAF6 protein; METTL3 overexpression activates the TRAF6-NF-κB pathway in an m6A-dependent manner to promote LPS-induced microglial inflammation. Co-immunoprecipitation (METTL3-TRAF6), MeRIP-qPCR for TRAF6 3'-UTR, dot blot for global m6A, siRNA knockdown, NF-κB signaling western blot Neuroreport Low 33165191
2021 METTL3-mediated m6A modification of SNAP29 mRNA destabilizes it, depleting SNAP29 protein; this disrupts autophagic flux (SNARE-dependent autophagosome-lysosome fusion), increases ROS, and promotes parthanatos in ischemic flap cells. YTHDF2 recognizes SNAP29 m6A sites to mediate its degradation. MeRIP-qPCR, RIP-qPCR, RNA stability assay, METTL3/YTHDF2 knockdown, AAV-SNAP29 rescue, ischemic flap mouse model Autophagy Medium 40340690
2024 Mettl3 determines pancreatic endocrine lineage fate by targeting Hdac1 mRNA for m6A modification in bipotent progenitors; loss of Hdac1 causes aberrant activation of Wnt/Notch signaling and blocks endocrine differentiation. Pancreatic progenitor-specific Mettl3 KO leads to loss of Ngn3+ endocrine progenitors and increased Sox9+ ductal precursors. Pdx1-Cre Mettl3 KO mice, m6A profiling, Hdac1 mRNA stability and m6A assay, Wnt/Notch signaling analysis, in vitro embryonic pancreatic culture rescue experiments Diabetes Medium 37963393
2024 METTL3-mediated m6A modification of YTHDF2-recognized m6A sites on SLC7A11 mRNA promotes its degradation, thereby inducing ferroptosis in macrophages. This pathway is driven upstream by EP300-mediated H3K18 lactylation binding to the METTL3 promoter in response to lactate accumulation in atherosclerosis. H3K18la ChIP-qPCR at METTL3 promoter, MeRIP for SLC7A11, YTHDF2 RIP, myeloid-specific Mettl3 KO mice (ApoE−/−), ferroptosis markers Biochimica et biophysica acta. General subjects Medium 40588140
2024 METTL3 increases m6A modification on TERRA in ALT+ cancer cells; the m6A-mediated recruitment of hnRNPA2B1 to TERRA is critical for R-loop formation at telomeres. Loss of METTL3 or TERRA m6A reduces R-loops, causes telomere damage and shortening. METTL3 inhibition with a BBB-penetrant inhibitor compromises telomere targeting of TERRA in ALT+ neuroblastoma cells. m6A-seq of TERRA, hnRNPA2B1 RIP-seq, DRIP (R-loop detection), METTL3 inhibitor (STM2457), telomere damage assay (γH2AX at telomeres), ALT+ neuroblastoma cell lines Nucleic acids research High 38180812
2021 In Xenopus, Mettl3 knockdown causes anteriorization of neural patterning, loss of neural crest specification, and impaired neuronal differentiation; m6A-dependent mRNA destabilization (via Ythdf1 and mRNA decay factors Lsm1/Tut7) regulates posteriorizing WNT signaling during neurulation. Mettl3 morpholino knockdown in Xenopus, Ythdf1/Lsm1/Tut7 knockdowns, neural marker in situ hybridization, WNT reporter assay Molecular and cellular biology Medium 33972392
2023 METTL3 promotes m6A modification of pri-miR-148a-3p in prostate cancer cells, facilitating its processing and maturation (consistent with DGCR8-mediated mechanism), thereby upregulating miR-148a-3p levels. MeRIP assay for pri-miR-148a-3p, METTL3 siRNA knockdown, miRNA qRT-PCR, in vivo xenograft Environmental toxicology Low 37449729
2022 METTL3-mediated m6A modification of TRAF6 mRNA enhances its expression in osteosarcoma cells, and TRAF6 upregulation promotes OS metastasis; METTL3 depletion reduces TRAF6 expression and metastatic activity. Transcriptome sequencing and m6A-seq, RIP, dual-luciferase assay, wound healing/invasion, in vivo tumorigenic assay Journal of bone oncology Low 35145841
2022 METTL3 promotes m6A modification of CXCL5 mRNA (stabilizing it) and suppresses CCL5 expression in an m6A-dependent manner in bladder cancer cells, leading to increased MDSC recruitment and reduced CD8+ T cell infiltration in the tumor microenvironment. shRNA silencing of METTL3, RNA-seq, MeRIP-seq, RNA degradation assay, ELISA for chemokines, flow cytometry in orthotopic and ectopic mouse models Journal for immunotherapy of cancer Medium 40234090
2023 METTL3-mediated m6A modification of BATF mRNA stabilizes it (via IGF2BP2), elevating BATF expression in microglia; BATF directly binds promoters of inflammatory cytokine and chemokine genes to drive pro-inflammatory programs and TNF-dependent neurotoxicity. MeRIP-seq, IGF2BP2 RIP, CUT&Tag for BATF chromatin binding, selective microglial Mettl3 ablation, cytokine measurement (TBI mouse model) Cell death and differentiation High 38902548
2024 METTL3-mediated m6A modification of OTUD1 mRNA promotes its stability and increases OTUD1 protein expression; OTUD1 deubiquitinates PGAM5, robustly activating the Ask1-p38/JNK signaling pathway to drive pathological cardiac hypertrophy. RIP for METTL3-OTUD1 interaction, RNA stability assay, cardiac-specific Otud1 KO/OE mice, TAC model, IP-mass spectrometry for OTUD1 substrates, deubiquitinase activity assay International journal of biological sciences Medium 39309432
2024 METTL3-mediated m6A modification of FOSL1 mRNA increases FOSL1 expression in an IGF2BP2-dependent manner in trophoblast cells; elevated FOSL1 suppresses trophoblast invasion and migration, contributing to fetal growth restriction. Pharmacological METTL3 inhibition (STM2457) restores trophoblast function and fetal weight in vivo. MeRIP-seq and RNA-seq of METTL3-KD trophoblasts, IGF2BP2 RIP, RNA stability assay, METTL3 OE in HTR8/SVneo, STM2457 treatment in FGR mouse model FASEB journal Medium 39565355
2023 METTL3-mediated m6A modification of SIRT1 mRNA is recognized by YTHDF2, inducing SIRT1 mRNA degradation; reduced SIRT1 inhibits FOXO3a signaling, promotes cellular senescence, and impairs ectopic endometrial stromal cell implantation. In vivo, Mettl3 conditional KO enhances SIRT1 and suppresses endometriosis. MeRIP-seq, RIP-qPCR, RNA stability assay, YTHDF2 RIP, PgrCre/Mettl3−/− mice and nude mouse xenograft model, senescence SA-β-gal assay Journal of translational medicine Medium 37353804
2024 METTL3-mediated m6A modification increases HSPA9 mRNA stability and translation efficiency in cervical cancer cells; exosomally secreted mortalin (HSPA9) blocks p53 nuclear transport, preventing p53-Gadd45A interaction and inactivating p53 to suppress senescence and promote malignant transformation. MeRIP (m6A sites in HSPA9 3'UTR), RNA stability assay, translation efficiency assay, exosome isolation, p53 nuclear fractionation, co-IP for p53-Gadd45A interaction, in vivo xenograft Cancer letters Medium 38253218
2022 METTL3-mediated m6A modification of TIMP2 mRNA in podocytes increases TIMP2 stability in an IGF2BP2-dependent manner, activating Notch signaling and promoting podocyte inflammation and apoptosis in diabetic nephropathy. Podocyte-conditional Mettl3 KO reduces podocyte injury and albuminuria in diabetic mice. MeRIP-qPCR, IGF2BP2 RIP, RNA stability assay, podocyte-specific Mettl3 KO mice (STZ model, db/db), AAV9-shMETTL3 therapeutic silencing Molecular therapy Medium 34995800
2023 METTL3 promotes m6A modification of LATS1 mRNA, which is recognized by YTHDF2 to reduce LATS1 mRNA stability, suppressing Hippo pathway activity and activating YAP/TAZ to promote breast cancer tumorigenesis and glycolysis. MeRIP-seq, RNA-seq, metabolomics-seq, RNA pulldown, RIP-qPCR, MeRIP-qPCR, RNA stability analysis, METTL3/YTHDF2 KO with YAP/TAZ localization assay Journal of experimental & clinical cancer research Medium 36609396
2023 METTL3 promotes m6A modification of EGR1 mRNA; IGF2BP2 binds to the m6A modification site, enhancing EGR1 mRNA stability and increasing EGR1 protein levels, which suppresses the JAK2/STAT3 pathway, disrupts mitophagy and mitochondrial dynamics, and exacerbates myocardial I/R injury. MeRIP-qPCR, IGF2BP2 RIP, EGR1 mRNA stability assay, H/R cardiomyocyte model, I/R mouse model, JAK2/STAT3 signaling western blot Cell biology and toxicology Low 39707117
2022 METTL3 promotes m6A modification on TRAF6 mRNA in cardiomyocytes/microglia of the PVN, increasing TRAF6 expression; METTL3 inhibition prevents TRAF6 translocation to mitochondria and blocks the TRAF6/ECSIT pathway, reducing mitochondrial ROS and sympathetic hyperactivity post-myocardial infarction. MeRIP for TRAF6 in PVN microglia, TRAF6 mitochondrial fractionation, METTL3 inhibitor in vivo, RSNA/NE measurement, programmed electrical stimulation Free radical biology & medicine Low 37898386
2023 METTL3-mediated m6A modification of STAT1 transcripts promotes their degradation in γδ T cells, preventing over-activation of STAT1 signaling; additionally, METTL3 prevents formation of immunostimulatory endogenous double-stranded RNAs. Mettl3-KO in γδ T cells, Stat1 mRNA decay assay, dsRNA detection (J2 antibody), STAT1 protein/mRNA measurement, IL-17 ELISA Cell reports Medium 37355989
2023 METTL3-mediated m6A modification of PINK1 mRNA promotes its degradation in a YTHDF2-dependent manner in renal tubular cells, impairing PINK1-Parkin mitophagy and exacerbating diabetic nephropathy. MeRIP-qPCR for PINK1 m6A, RIP for YTHDF2-PINK1, METTL3 siRNA, PINK1 mRNA stability assay, mitophagy markers (LC3, p62), in vivo DKD model Journal of diabetes investigation Low 38013600
2024 METTL3 promotes m6A modification on SNAIL mRNA in colorectal cancer cells; YTHDF1 reads this m6A to promote SNAIL translation, which activates NF-κB to increase CXCL2 secretion, recruiting M2 macrophages to facilitate pulmonary metastasis. MeRIP-qPCR for SNAIL, RIP for YTHDF1-SNAIL, RNA stability assay, luciferase reporter for NF-κB, ELISA for CXCL2, macrophage co-culture, in vivo metastasis model Journal of experimental & clinical cancer research Low 38605400
2024 METTL3-mediated m6A modification of ACVR2A mRNA represses its synthesis in skeletal muscle, blunting activin/myostatin anti-hypertrophic signaling; this represents a m6A-dependent post-transcriptional mechanism controlling muscle size. (Supporting the finding in PMID 35013323 with additional mechanistic detail.) m6A-seq, METTL3 conditional KO, ACVR2A protein measurement, myostatin inhibitor rescue, AAV-METTL3 delivery Nature communications High 35013323

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Molecular cell 1276 27117702
2022 Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Molecular cell 660 35320754
2019 Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation. Nature communications 438 31015515
2019 METTL3 and ALKBH5 oppositely regulate m6A modification of TFEB mRNA, which dictates the fate of hypoxia/reoxygenation-treated cardiomyocytes. Autophagy 418 30870073
2021 METTL3-mediated m6A modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Annals of the rheumatic diseases 320 34706873
2018 SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function. Nucleic acids research 277 29506078
2022 Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms. Science translational medicine 262 35417191
2018 METTL3-mediated m6A modification is required for cerebellar development. PLoS biology 237 29879109
2024 Histone lactylation-regulated METTL3 promotes ferroptosis via m6A-modification on ACSL4 in sepsis-associated lung injury. Redox biology 225 38852200
2022 Fusobacterium nucleatum reduces METTL3-mediated m6A modification and contributes to colorectal cancer metastasis. Nature communications 213 35273176
2021 METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection. Cell reports 213 33961823
2022 METTL3-mediated m6A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy. Molecular therapy : the journal of the American Society of Gene Therapy 174 34995800
2020 METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA. Nucleic acids research 157 33035345
2021 METTL3-dependent m6A modification programs T follicular helper cell differentiation. Nature communications 151 33637761
2019 The RNA m6A methyltransferase METTL3 promotes pancreatic cancer cell proliferation and invasion. Pathology, research and practice 129 31606241
2020 Altered Expression of the m6A Methyltransferase METTL3 in Alzheimer's Disease. eNeuro 120 32847866
2019 The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1. Biochemical and biophysical research communications 117 31253399
2023 The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer. Journal of experimental & clinical cancer research : CR 97 36609396
2022 The m6A methyltransferase METTL3 promotes LPS-induced microglia inflammation through TRAF6/NF-κB pathway. Neuroreport 97 33165191
2022 METTL3-mediated m6A modification stabilizes TERRA and maintains telomere stability. Nucleic acids research 92 36399511
2022 METTL3 promotes colorectal carcinoma progression by regulating the m6A-CRB3-Hippo axis. Journal of experimental & clinical cancer research : CR 89 35012593
2021 METTL3/YTHDF2 m6A axis accelerates colorectal carcinogenesis through epigenetically suppressing YPEL5. Molecular oncology 75 33411363
2022 m6A methyltransferase METTL3-induced lncRNA SNHG17 promotes lung adenocarcinoma gefitinib resistance by epigenetically repressing LATS2 expression. Cell death & disease 74 35902569
2023 METTL3-mediated m6A mRNA methylation regulates neutrophil activation through targeting TLR4 signaling. Cell reports 67 36920907
2020 METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP. Cell biology international 67 32869897
2022 Alternative splicing of METTL3 explains apparently METTL3-independent m6A modifications in mRNA. PLoS biology 62 35853000
2022 The m6A methyltransferase METTL3 regulates muscle maintenance and growth in mice. Nature communications 58 35013323
2020 Upregulation of METTL3 expression and m6A RNA methylation in placental trophoblasts in preeclampsia. Placenta 55 33070036
2023 Intracellular Fusobacterium nucleatum infection increases METTL3-mediated m6A methylation to promote the metastasis of esophageal squamous cell carcinoma. Journal of advanced research 53 37619934
2023 METTL3-mediated m6A modification of SIRT1 mRNA inhibits progression of endometriosis by cellular senescence enhancing. Journal of translational medicine 52 37353804
2023 METTL3-dependent m6A methylation facilitates uterine receptivity and female fertility via balancing estrogen and progesterone signaling. Cell death & disease 51 37270544
2024 METTL3 drives telomere targeting of TERRA lncRNA through m6A-dependent R-loop formation: a therapeutic target for ALT-positive neuroblastoma. Nucleic acids research 50 38180812
2024 The m6A methyltransferase METTL3 drives neuroinflammation and neurotoxicity through stabilizing BATF mRNA in microglia. Cell death and differentiation 48 38902548
2024 The ARID1A-METTL3-m6A axis ensures effective RNase H1-mediated resolution of R-loops and genome stability. Cell reports 47 38358891
2024 Targeting the m6A RNA methyltransferase METTL3 attenuates the development of kidney fibrosis. Experimental & molecular medicine 38 38297163
2025 METTL3-dependent m6A modification of SNAP29 induces "autophagy-mitochondrial crisis" in the ischemic microenvironment after soft tissue transplantation. Autophagy 35 40340690
2024 METTL3-mediated m6A modification increases Hspa1a stability to inhibit osteoblast aging. Cell death discovery 34 38538596
2024 METTL3 recruiting M2-type immunosuppressed macrophages by targeting m6A-SNAIL-CXCL2 axis to promote colorectal cancer pulmonary metastasis. Journal of experimental & clinical cancer research : CR 32 38605400
2023 METTL3/YTHDF2 m6A axis mediates the progression of diabetic nephropathy through epigenetically suppressing PINK1 and mitophagy. Journal of diabetes investigation 32 38013600
2022 METTL3 promotes glycolysis and cholangiocarcinoma progression by mediating the m6A modification of AKR1B10. Cancer cell international 31 36476503
2023 ZBTB7C m6A modification incurred by METTL3 aberration promotes osteosarcoma progression. Translational research : the journal of laboratory and clinical medicine 27 37121538
2023 METTL3-mediated m6A mRNA modification was involved in cadmium-induced liver injury. Environmental pollution (Barking, Essex : 1987) 27 37236586
2022 METTL3 promotes proliferation and myogenic differentiation through m6A RNA methylation/YTHDF1/2 signaling axis in myoblasts. Life sciences 27 35351467
2024 METTL3-mediated m6A modification of LINC00520 confers glycolysis and chemoresistance in osteosarcoma via suppressing ubiquitination of ENO1. Cancer letters 26 39168299
2024 KMT2A regulates the autophagy-GATA4 axis through METTL3-mediated m6A modification of ATG4a to promote NPCs senescence and IVDD progression. Bone research 26 39572532
2024 The m6A methyltransferase METTL3 drives thyroid cancer progression and lymph node metastasis by targeting LINC00894. Cancer cell international 25 38291427
2024 METTL3-mediated HSPA9 m6A modification promotes malignant transformation and inhibits cellular senescence by regulating exosomal mortalin protein in cervical cancer. Cancer letters 24 38253218
2024 Intracellular C5aR1 inhibits ferroptosis in glioblastoma through METTL3-dependent m6A methylation of GPX4. Cell death & disease 24 39368999
2024 METTL3-mediated m6A modification enhances lncRNA H19 stability to promote endothelial cell inflammation and pyroptosis to aggravate atherosclerosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 39432244
2024 METTL3 facilitates kidney injury through promoting IRF4-mediated plasma cell infiltration via an m6A-dependent manner in systemic lupus erythematosus. BMC medicine 24 39501302
2023 METTL3-mediated m6A methylation orchestrates mRNA stability and dsRNA contents to equilibrate γδ T1 and γδ T17 cells. Cell reports 24 37355989
2023 Mettl3-catalyzed m6A regulates histone modifier and modification expression in self-renewing somatic tissue. Science advances 24 37656787
2021 METTL3-mediated m6A methylation of ASPM drives hepatocellular carcinoma cells growth and metastasis. Journal of clinical laboratory analysis 24 34398984
2021 The M6A methyltransferase METTL3 regulates proliferation in esophageal squamous cell carcinoma. Biochemical and biophysical research communications 24 34624569
2024 METTL3-mediated m6A modification of SIRT1 mRNA affects the progression of diabetic cataracts through cellular autophagy and senescence. Journal of translational medicine 23 39334185
2023 METTL3-Mediated m6A Modification Controls Splicing Factor Abundance and Contributes to Aggressive CLL. Blood cancer discovery 20 37067905
2023 METTL3-mediated m6A methylation regulates ovarian cancer progression by recruiting myeloid-derived suppressor cells. Cell & bioscience 20 37932814
2022 Mechanism of METTL3-mediated m6A modification in depression-induced cognitive deficits. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 19 35591810
2025 METTL3-mediated m6A modification of SLC7A11 enhances nasopharyngeal carcinoma radioresistance by inhibiting ferroptosis. International journal of biological sciences 18 39990661
2023 m6A methyltransferase METTL3 contributes to sympathetic hyperactivity post-MI via promoting TRAF6-dependent mitochondrial ROS production. Free radical biology & medicine 18 37898386
2023 m6A methyltransferase METTL3 facilitates multiple myeloma cell growth through the m6A modification of BZW2. Annals of hematology 17 37222774
2023 METTL3 Mediated MALAT1 m6A Modification Promotes Proliferation and Metastasis in Osteosarcoma Cells. Molecular biotechnology 17 37897586
2022 The m6A methyltransferase METTL3 promotes trophoblast cell invasion by regulating MYLK expression. Placenta 17 36170767
2024 RNA Binding by the m6A Methyltransferases METTL16 and METTL3. Biology 16 38927271
2025 Spatial control of m6A deposition on enhancer and promoter RNAs through co-acetylation of METTL3 and H3K27 on chromatin. Molecular cell 15 40101711
2024 Increased m6A RNA methylation and METTL3 expression may contribute to the synovitis progression of rheumatoid arthritis. Experimental cell research 15 39245197
2023 METTL3-mediated m6A modification of has_circ_0007905 promotes age-related cataract progression through miR-6749-3p/EIF4EBP1. PeerJ 15 36908822
2022 METTL3-mediated RNA m6A Hypermethylation Promotes Tumorigenesis and GH Secretion of Pituitary Somatotroph Adenomas. The Journal of clinical endocrinology and metabolism 15 34491359
2022 m6A-dependent upregulation of TRAF6 by METTL3 is associated with metastatic osteosarcoma. Journal of bone oncology 15 35145841
2022 Roles of the m6A methyltransferases METTL3, METTL14, and WTAP in pulmonary tuberculosis. Frontiers in immunology 15 36569923
2025 METTL3 promotes an immunosuppressive microenvironment in bladder cancer via m6A-dependent CXCL5/CCL5 regulation. Journal for immunotherapy of cancer 14 40234090
2024 The RNA m6A writer METTL3 in tumor microenvironment: emerging roles and therapeutic implications. Frontiers in immunology 14 38322265
2024 METTL3-mediated m6A modification of circGLIS3 promotes prostate cancer progression and represents a potential target for ARSI therapy. Cellular & molecular biology letters 14 39143552
2022 The "m6A writer" METTL3 and the "m6A reader" IGF2BP2 regulate cutaneous T-cell lymphomas progression via CDKN2A. Hematological oncology 14 35446451
2024 METTL3 mediated ferroptosis in chondrocytes and promoted pain in KOA via HMGB1 m6A modification. Cell biology international 13 39129231
2023 METTL3-mediated m6A methylation regulates granulosa cells autophagy during follicular atresia in pig ovaries. Theriogenology 13 36857977
2023 METTL3-mediated m6A modification of pri-miR-148a-3p affects prostate cancer progression by regulating TXNIP. Environmental toxicology 13 37449729
2023 Decreased expression of Chrna4 by METTL3-mediated m6A modification participates in BPA-induced spatial memory deficit. Environmental research 13 37495067
2023 METTL3-Mediated RNA m6A Modification Regulates the Angiogenic Behaviors of Retinal Endothelial Cells by Methylating MMP2 and TIE2. Investigative ophthalmology & visual science 12 37819742
2023 METTL3/IGF2BP3-regulated m6A modification of HYOU1 confers doxorubicin resistance in breast cancer. Biochimica et biophysica acta. General subjects 12 38103759
2025 EP300-mediated H3K18la regulation of METTL3 promotes macrophage ferroptosis and atherosclerosis through the m6A modification of SLC7A11. Biochimica et biophysica acta. General subjects 11 40588140
2024 METTL3 regulates M6A methylation-modified EBV-pri-miR-BART3-3p to promote NK/T cell lymphoma growth. Cancer letters 11 38880226
2023 METTL3/YTHDF2 m6A axis promotes the malignant progression of bladder cancer by epigenetically suppressing RRAS. Oncology reports 11 36960869
2023 m6A Writer METTL3-Mediated lncRNA LINC01125 Prevents the Malignancy of Papillary Thyroid Cancer. Critical reviews in immunology 11 37824376
2022 Overexpression of m6A-factors METTL3, ALKBH5, and YTHDC1 alters HPV16 mRNA splicing. Virus genes 11 35190939
2021 RNA m6A Methyltransferase Mettl3 Regulates Spatial Neural Patterning in Xenopus laevis. Molecular and cellular biology 11 33972392
2024 Mettl3-Mediated m6A Methylation Controls Pancreatic Bipotent Progenitor Fate and Islet Formation. Diabetes 10 37963393
2024 METTL3 inhibits BMSC apoptosis and facilitates osteonecrosis repair via an m6A-IGF2BP2-dependent mechanism. Heliyon 10 38784565
2024 METTL3-mediated m6A modification of OTUD1 aggravates press overload induced myocardial hypertrophy by deubiquitinating PGAM5. International journal of biological sciences 10 39309432
2024 METTL3 accelerates staphylococcal protein A (SpA)-induced osteomyelitis progression by regulating m6A methylation-modified miR-320a. Journal of orthopaedic surgery and research 10 39506767
2024 METTL3, m6A modification, and EGR1: interplay affecting myocardial I/R injury outcomes. Cell biology and toxicology 10 39707117
2023 METTL3-mediated m6A modification of circRNF220 modulates miR-330-5p/survivin axis to promote osteosarcoma progression. Journal of cancer research and clinical oncology 10 37838643
2023 METTL3-mediated m6A RNA methylation was involved in aluminum-induced neurotoxicity. Ecotoxicology and environmental safety 10 38150748
2022 METTL3-mediated m6A RNA methylation regulates dorsal lingual epithelium homeostasis. International journal of oral science 10 35581183
2025 Bacteroides fragilis Toxin Suppresses METTL3-Mediated m6A Modification in Macrophage to Promote Inflammatory Bowel Disease. Journal of Crohn's & colitis 9 40065724
2024 METTL3 and IGF2BP1-Mediated m6A Modification of ZHX2 Promotes Tumor Property of Renal Cell Carcinoma. Kidney & blood pressure research 9 39159608
2024 METTL3 and IGF2BP2 coordinately regulate FOSL1 mRNA via m6A modification, suppressing trophoblast invasion and contributing to fetal growth restriction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 39565355
2024 EZH2 promotes B-cell autoimmunity in primary Sjogren's syndrome via METTL3-mediated m6A modification. Journal of autoimmunity 9 39577129
2024 Exercise promotes skeletal muscle growth in adolescents via modulating Mettl3-mediated m6A methylation of MyoD in muscle satellite cells. Cellular & molecular biology letters 9 39633280
2023 m6A methyltransferase METTL3 inhibits endometriosis by regulating alternative splicing of MIR17HG. Reproduction (Cambridge, England) 9 36445237

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