{"doi":"10.1016/j.ymthe.2020.09.018","title":"METTL3-Regulated m6A Epitranscriptome Plasticity in Pathological Angiogenesis","abstract":"In recent years, there have been major advances in our knowledge of the biochemistry and molecular regulations of the N6-methyladenosine (m6A) RNA epitranscriptome in diverse physiological processes. Nevertheless, the functional significance of m6A in the context of pathological manifestations is heavily understudied, impeding our understanding of the role of m6A in disease processes. Particularly, there are very few investigations of the regulatory mechanisms of m6A in physiological and pathological angiogenesis, the process of formation of new blood vessels, which plays a critical role in development, tissue ischemia, diabetes, and cancer. In this issue of Molecular Therapy, Yao et. al.1Yao M.D. Jiang Q. Ma Y. Liu C. Zhu C.Y. Sun Y.N. et al.Role of METTL3-Dependent N6-Methyladenosine mRNA Modification in the Promotion of Angiogenesis.Mol. Ther. 2020; 28 (this issue): 2191-2202Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar added a new dimension to this remarkable area of research to further our understanding of the epitranscriptomic mechanisms of pathological angiogenesis. The authors investigated the functional role of the m6A-writer METTL3-regulated m6A-methylome in endothelial cell (EC) angiogenesis in vitro and in mouse retinas in vivo using an EC-specific knock-out (KO) mouse model. m6A was found to be elevated in the transcriptome of ECs and mouse retinas following hypoxic stress. The authors attributed this increase to elevated METTL3 levels. Depletion of METTL3 decreased endothelial cell angiogenic ability, including viability, proliferation, migration and tube formation in vitro. Post-synthesis, RNA molecules undergo many different modifications that have the potential to alter their function and stability. m6A is one of the more prevalent, functionally relevant, and better characterized internal modification in mRNA. m6A is known to be actively regulated and has emerged as an essential and widespread regulatory mechanism controlling gene expression post-transcriptionally. The functions of m6A methyltransferases (writers), demethylases (erasers), and specific binding proteins (readers) have been studied extensively in a range of systems, revealing regulatory roles in a context-dependent manner. METTL3 is a methyltransferase that acts as the main catalytic subunit in a complex with METTL14 (m6A writer complex) to deposit m6A, which is responsible for the vast majority of m6A on mRNAs. In this new study, the authors demonstrate that EC-specific deletion of METTL3 decreases the vascular area and pathological neovascular tufts in two models in vivo: an oxygen-induced retinopathy model and an alkali-burn-induced corneal neovascularization model. Interestingly, METTL3 silencing resulted in aberrant Wnt signaling, leading to decreased levels of pathological neovascularization in oxygen-induced proliferative retinopathy. Mechanistically, m6A target genes LRP6 and DVL1 are dysregulated by the m6A reader protein YTH-m6A RNA-binding protein1 (YTHDF1) to affect Wnt signaling. The authors observe that intervention of Wnt signaling via regulating m6A methylation is critical for vascular homeostasis. The authors have concluded that “enhanced m6A RNA methylation contributes to the progression of pathological angiogenesis, whereas decreased m6A methylation alleviates vascular dysfunction, highlighting the importance of m6A methylation in vascular homeostasis.” Findings from this article align with the observations that high m6A is detected in cancerous tissues with high levels of hypoxia-induced angiogenesis. In the same line, METTL3 levels were found to be elevated in lung adenocarcinoma cell lines compared to healthy tissues, whereas its depletion led to inhibition of cancer cell growth, decreased viability, and increased apoptosis. High expression of METTL3 in cancer cells is known to promote translation of several oncogenes. Contrasting reports show that the m6A writer complex has important oncogenic and tumor","journal":"Molecular Therapy","year":2020,"id":116935,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":545863,"name":"Susmita Sahoo","orcid":"0000-0002-7279-1564","position":0,"is_corresponding":true}],"reference_count":3,"raw_metadata":null,"created_at":"2026-07-18T23:13:47.803267Z","pmid":"32966773","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}