{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Hsu KW"],"funding":["Ministry of Science and Technology, Taiwan","Howard Hughes Medical Institute","Chang Gung Memorial Hospital, Linkou"],"pagination":["249"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9716733"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["23(1)"],"pubmed_abstract":["<h4>Background</h4>DNA N6-methyldeoxyadenosine (6mA) is rarely present in mammalian cells and its nuclear role remains elusive.<h4>Results</h4>Here we show that hypoxia induces nuclear 6mA modification through a DNA methyltransferase, METTL4, in hypoxia-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. Co-expression of METTL4 and 6mA represents a prognosis marker for upper tract urothelial cancer patients. By RNA sequencing and 6mA chromatin immunoprecipitation-exonuclease digestion followed by sequencing, we identify lncRNA RP11-390F4.3 and one novel HIF-1α co-activator, ZMIZ1, that are co-regulated by hypoxia and METTL4. Other genes involved in hypoxia-mediated phenotypes are also regulated by 6mA modification. Quantitative chromatin isolation by RNA purification assay shows the occupancy of lncRNA RP11-390F4.3 on the promoters of multiple EMT regulators, indicating lncRNA-chromatin interaction. Knockdown of lncRNA RP11-390F4.3 abolishes METTL4-mediated tumor metastasis. We demonstrate that ZMIZ1 is an essential co-activator of HIF-1α.<h4>Conclusions</h4>We show that hypoxia results in enriched 6mA levels in mammalian tumor cells through METTL4. This METTL4-mediated nuclear 6mA deposition induces tumor metastasis through activating multiple metastasis-inducing genes. METTL4 is characterized as a potential therapeutic target in hypoxic tumors."],"journal":["Genome biology"],"pubmed_title":["METTL4-mediated nuclear N6-deoxyadenosine methylation promotes metastasis through activating multiple metastasis-inducing targets."],"pmcid":["PMC9716733"],"funding_grant_id":["OMRPG3I0013","MOST 110-2628-B-039-007","MOST 110-2326-B-182A-004"],"pubmed_authors":["Pang ST","He C","Peng PH","Lee DY","Hsu KW","Chung CJ","Cui XL","Huang CH","Chang CH","Tsai YC","Chang JS","Chen JL","Lai JC","Hao Z","Chang H","Wu KJ"],"additional_accession":[]},"is_claimable":false,"name":"METTL4-mediated nuclear N6-deoxyadenosine methylation promotes metastasis through activating multiple metastasis-inducing targets.","description":"<h4>Background</h4>DNA N6-methyldeoxyadenosine (6mA) is rarely present in mammalian cells and its nuclear role remains elusive.<h4>Results</h4>Here we show that hypoxia induces nuclear 6mA modification through a DNA methyltransferase, METTL4, in hypoxia-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. Co-expression of METTL4 and 6mA represents a prognosis marker for upper tract urothelial cancer patients. By RNA sequencing and 6mA chromatin immunoprecipitation-exonuclease digestion followed by sequencing, we identify lncRNA RP11-390F4.3 and one novel HIF-1α co-activator, ZMIZ1, that are co-regulated by hypoxia and METTL4. Other genes involved in hypoxia-mediated phenotypes are also regulated by 6mA modification. Quantitative chromatin isolation by RNA purification assay shows the occupancy of lncRNA RP11-390F4.3 on the promoters of multiple EMT regulators, indicating lncRNA-chromatin interaction. Knockdown of lncRNA RP11-390F4.3 abolishes METTL4-mediated tumor metastasis. We demonstrate that ZMIZ1 is an essential co-activator of HIF-1α.<h4>Conclusions</h4>We show that hypoxia results in enriched 6mA levels in mammalian tumor cells through METTL4. This METTL4-mediated nuclear 6mA deposition induces tumor metastasis through activating multiple metastasis-inducing genes. METTL4 is characterized as a potential therapeutic target in hypoxic tumors.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2025-04-04T13:46:24.277Z","creation":"2025-04-04T13:46:24.277Z"},"accession":"S-EPMC9716733","cross_references":{"pubmed":["36461076"],"doi":["10.1186/s13059-022-02819-3"]}}