ArticlePLoS biology2022
Alternative splicing of METTL3 explains apparently METTL3-independent m6A modifications in mRNA.
Article in PLoS biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 70 citations in OpenAlex.
- METTL14 inhibits atherogenesis by epigenetically activating PPAR-α/γ transcription and fatty acid oxidation in VSMCs.Cardiovascular research · 2026Article
- Nanopore direct RNA sequencing and the epitranscriptome: Advances in mapping native RNA landscapes.iMeta · 2026Review
- m6A epigenetic modification of viral RNA is critical for the transmission cycle of mosquito-borne flaviviruses.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The new era of single-molecule RNA modification detection through nanopore base-calling models.Nature reviews. Molecular cell biology · 2026Review
- The methyltransferase-like proteins as core regulators of nucleic acid modifications and post-translation modification of proteins in disease pathogenesis and therapeutic implications.Biomarker research · 2025Review
- A portable poison exon for small-molecule control of mammalian gene expression.Nature methods · 2025Article
- Why does the m6A writer complex require so many proteins?PLoS biology · 2025Review
- Article
- mCell · 2025Article
- Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia.Cell reports · 2025Article
- mCommunications biology · 2025Article
- Global analysis by LC-MS/MS ofRNA (New York, N.Y.) · 2025Article
- The role of NJournal of virology · 2025Review
- De novo basecalling of RNA modifications at single molecule and nucleotide resolution.Genome biology · 2025Article
- m6A epitranscriptomic modification in hepatocellular carcinoma: implications for the tumor microenvironment and immunotherapy.Frontiers in immunology · 2025Review
- Alterations Expression of Key RNA Methylation (m6A) Enzymes in Testicular Tissue of Rats with Induced Varicocele.Reproductive sciences (Thousand Oaks, Calif.) · 2025Article
- Unveiling the dynamics and therapeutic potential of mInternational journal of biological sciences · 2025Review
- RNA-Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post-Transcriptional Manner.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Structure-optimized sgRNA selection with PlatinumCRISPr for efficient Cas9 generation of knockouts.Genome research · 2024Article
- FUS and METTL3 collaborate to regulate RNA maturation, preventing unfolded protein response and promoting gastric cancer progression.Clinical and experimental medicine · 2024Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
N6-methyladenosine (m6A) is a highly prevalent mRNA modification that promotes degradation of transcripts encoding proteins that have roles in cell development, differentiation, and other pathways. METTL3 is the major methyltransferase that catalyzes the formation of m6A in mRNA. As 30% to 80% of m6A can remain in mRNA after METTL3 depletion by CRISPR/Cas9-based methods, other enzymes are thought to catalyze a sizable fraction of m6A. Here, we reexamined the source of m6A in the mRNA transcriptome. We characterized mouse embryonic stem cell lines that continue to have m6A in their mRNA after Mettl3 knockout. We show that these cells express alternatively spliced Mettl3 transcript isoforms that bypass the CRISPR/Cas9 mutations and produce functionally active methyltransferases. We similarly show that other reported METTL3 knockout cell lines express altered METTL3 proteins. We find that gene dependency datasets show that most cell lines fail to proliferate after METTL3 deletion, suggesting that reported METTL3 knockout cell lines express altered METTL3 proteins rather than have full knockout. Finally, we reassessed METTL3's role in synthesizing m6A using an exon 4 deletion of Mettl3 and found that METTL3 is responsible for >95% of m6A in mRNA. Overall, these studies suggest that METTL3 is responsible for the vast majority of m6A in the transcriptome, and that remaining m6A in putative METTL3 knockout cell lines is due to the expression of altered but functional METTL3 isoforms.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.