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They act by guiding RNA-induced silencing complexes to miRNA response elements (MREs) in target mRNAs, inducing translational inhibition and\/or mRNA degradation. Functional MREs are expected to predominantly occur in the 3\u2032 untranslated region and involve perfect base-pairing of the miRNA seed. Here, we generate a high-resolution map of miR-181a\/b-1 (miR-181) MREs to define the targeting rules of miR-181 in developing murine T\u00a0cells. By combining a multi-omics approach with computational high-resolution analyses, we uncover novel miR-181 targets and demonstrate that miR-181 acts predominantly through RNA destabilization. Importantly, we discover an alternative seed match and identify a distinct set of targets with repeat elements in the coding sequence which are targeted by miR-181 and mediate translational inhibition. In conclusion, deep profiling of MREs in primary cells is critical to expand physiologically relevant targetomes and establish context-dependent miRNA targeting rules.<\/jats:p>","DOI":"10.1093\/nar\/gkae416","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T09:09:54Z","timestamp":1715677794000},"page":"8515-8533","source":"Crossref","is-referenced-by-count":16,"title":["A high-resolution map of functional miR-181 response elements in the thymus reveals the role of coding sequence targeting and an alternative seed match"],"prefix":"10.1093","volume":"52","author":[{"given":"Nikita A","family":"Verheyden","sequence":"first","affiliation":[{"name":"Molecular Immunology, Justus Liebig University Gie\u00dfen , 35392\u00a0 Gie\u00dfen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3122-1095","authenticated-orcid":false,"given":"Melina","family":"Klostermann","sequence":"additional","affiliation":[{"name":"Buchmann Institute for Molecular Life Sciences & Institute of Molecular Biosciences, Goethe University Frankfurt , 60438\u00a0 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1778-0248","authenticated-orcid":false,"given":"Mirko","family":"Br\u00fcggemann","sequence":"additional","affiliation":[{"name":"Buchmann Institute for Molecular Life Sciences & Institute of Molecular Biosciences, Goethe University Frankfurt , 60438\u00a0 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna\u00a0M","family":"Steede","sequence":"additional","affiliation":[{"name":"Molecular Immunology, Justus Liebig University Gie\u00dfen , 35392\u00a0 Gie\u00dfen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anica","family":"Scholz","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt , 60590\u00a0 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shady","family":"Amr","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt , 60590\u00a0 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Lichtenthaeler","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, Faculty of Medicine, Goethe University Frankfurt , 60590\u00a0 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"M\u00fcnch","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry II, Faculty of Medicine, Goethe University Frankfurt , 60590\u00a0 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1952-5259","authenticated-orcid":false,"given":"Tobias","family":"Schmid","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt , 60590\u00a0 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3527-3378","authenticated-orcid":false,"given":"Kathi","family":"Zarnack","sequence":"additional","affiliation":[{"name":"Buchmann Institute for Molecular Life Sciences & Institute of Molecular Biosciences, Goethe University Frankfurt , 60438\u00a0 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7873-7334","authenticated-orcid":false,"given":"Andreas","family":"Krueger","sequence":"additional","affiliation":[{"name":"Molecular Immunology, Justus Liebig University Gie\u00dfen , 35392\u00a0 Gie\u00dfen , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,5,23]]},"reference":[{"key":"2024081200011206400_B1","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"MicroRNAs: genomics, biogenesis, mechanism, and function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"2024081200011206400_B2","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/s41576-023-00611-y","article-title":"microRNAs in action: biogenesis, function and regulation","volume":"24","author":"Shang","year":"2023","journal-title":"Nat. Rev. Genet."},{"key":"2024081200011206400_B3","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1111\/febs.16422","article-title":"The intricate balance between microRNA-induced mRNA decay and translational repression","volume":"290","author":"Naeli","year":"2023","journal-title":"FEBS J"},{"key":"2024081200011206400_B4","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.tcb.2022.07.007","article-title":"Argonaute-dependent ribosome-associated protein quality control","volume":"33","author":"Gao","year":"2023","journal-title":"Trends Cell Biol."},{"key":"2024081200011206400_B5","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1038\/s41594-018-0136-3","article-title":"A novel class of microRNA-recognition elements that function only within open reading frames","volume":"25","author":"Zhang","year":"2018","journal-title":"Nat. Struct. Mol. 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