title: Widespread and dynamic translational control of red blood cell development.
abstract: Cell development requires tight yet dynamic control of protein production. Here, we use parallel RNA and ribosome profiling to study translational regulatory dynamics during murine terminal erythropoiesis. Our results uncover pervasive translational control of protein synthesis, with widespread alternative translation initiation and termination, robust discrimination of long noncoding from micropeptide-encoding RNAs, and dynamic use of upstream open reading frames. Further, we identify hundreds of messenger RNAs (mRNAs) whose translation efficiency is dynamically controlled during erythropoiesis and that enrich for target sites of RNA-binding proteins that are specific to hematopoietic cells, thus unraveling potential regulators of erythroid translational programs. A major such program involves enhanced decoding of specific mRNAs that are depleted in terminally differentiating/enucleating cells with decreasing transcriptional capacity. We find that RBM38, an erythroid-specific RNA-binding protein previously implicated in splicing, interacts with the general translation initiation factor eIF4G and promotes translation of a subset of these irreplaceable mRNAs. Inhibition of RBM38 compromises translation in erythroblasts and impairs their maturation, highlighting a key function for this protein during erythropoiesis. These findings thus reveal critical roles for dynamic translational control in supporting specialized mammalian cell formation.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Harvard University, Cambridge, MA; and.
authors.forename: Juan R
authors.identifier: 0000-0002-7136-2311
authors.initials: JR
authors.lastname: Alvarez-Dominguez
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN.
authors.forename: Wenqian
authors.identifier: 0000-0003-3577-3604
authors.initials: W
authors.lastname: Hu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology* / Q000378:metabolism; D004920:Erythropoiesis; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D016366:Open Reading Frames; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C491779:Elf4 protein, mouse; D012333:RNA, Messenger; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; C547649:Rbm38 protein, mouse; D014157:Transcription Factors