Widespread and dynamic translational control of red blood cell development

Cell development requires tight yet dynamic control of protein production. Here, we use murine erythropoiesis as a model to study translational regulatory dynamics during mammalian cell differentiation. We uncover pervasive translational control of protein synthesis, including widespread alternative translation initiation and termination, stoichiometric synthesis, and dynamic use of upstream reading frames. We thus unravel translational regulatory programs during erythropoiesis, comprising hundreds of mRNAs with dynamic translation efficiencies and their cell type-specific regulators. A major such program involves enhanced decoding of specific mRNAs depleted in terminally differentiating/enucleating cells with decreasing transcriptional capacity. Rbm38, an erythroid-specific RNA-binding protein, promotes translation of many such genes by recruiting the translation initiation factor eIF4G. Inhibiting Rbm38 blocks red cell production, and mice lacking Rbm38 develop anemia, demonstrating an essential role for Rbm38-mediated enhanced translation of irreplaceable mRNAs. These findings reveal critical roles for dynamic translational control in supporting specialized mammalian cell formation. Matched RNA-seq and Ribo-seq profiles of erythroid progenitors purified from E14.5 mouse fetal livers after 0, 24, 33, and 48 hours of ex vivo differentiation, generated by deep sequencing, in duplicate, using the Illumina HiSeq2000 platform.