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Here, we discovered that IRP2 deficiency reduced the expression of hypoxia-inducible factor 2\u03b1 (HIF2\u03b1) and its transcriptional target, EPO, thereby compromising the stress erythropoiesis response to generate red blood cells upon anemia. The distinct consequences of IRP2 and IRP1 on EPO result from the higher binding affinity of the HIF2\u03b1 IRE for IRP1 than IRP2. This difference in binding affinity arises from a bulge uridine in the upper stem of HIF2\u03b1 IRE that impairs the ability of IRP2 to bind the IRE. These results reveal that IRP1 and IRP2 play distinct roles in erythropoiesis and unveil an unsuspected IRE binding preference that contributes to the divergent phenotypes observed in IRP1- and IRP2-deficient mammals.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024025246","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T17:48:05Z","timestamp":1727200085000},"page":"533-542","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":8,"title":["A bulge uridine in the HIF2\u03b1 IRE allows IRP1 but not IRP2 to selectively regulate HIF2\u03b1 expression and ensuing EPO levels"],"prefix":"10.1182","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9478-5344","authenticated-orcid":false,"given":"De-Liang","family":"Zhang","sequence":"first","affiliation":[{"name":"1Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 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