A hierarchical network controls protein translation during murine embryonic stem cell self-renewal and differentiation.
Stem cell differentiation involves changes in transcription, but little is known about translational control during differentiation. We comprehensively profiled gene expression during differentiation of murine embryonic stem cells (ESCs) into embryoid bodies by integrating transcriptome analysis with global assessment of ribosome loading. While protein synthesis was parsimonious during self-renewal, differentiation induced an anabolic switch, with global increases in transcript abundance, polysome content, protein synthesis, and protein content. Furthermore, 78% of transcripts showed increased ribosome loading, thereby enhancing translational efficiency. Transcripts under exclusive translational control included the transcription factor ATF5, the tumor suppressor DCC, and the beta-catenin agonist Wnt1. We show that a hierarchy of translational regulators, including mTOR, 4EBP1, and the RNA-binding proteins DAZL and GRSF1, control global and selective protein synthesis during ESC differentiation. Parsimonious translation in pluripotent state and hierarchical translational regulation during differentiation may be important quality controls for self-renewal and choice of fate in ESCs.
Sampath
Prabha
P
Department of Pathology, Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA.
Pritchard
David K
DK
Pabon
Lil
L
Reinecke
Hans
H
Schwartz
Stephen M
SM
Morris
David R
DR
Murry
Charles E
CE
D051696:Activating Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D039642:Eukaryotic Initiation Factors; D020869:Gene Expression Profiling; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology; D046188:Protein Modification, Translational; D016601:RNA-Binding Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D051155:Wnt1 Protein / Q000096:biosynthesis / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
D051696:Activating Transcription Factors; D048868:Adaptor Proteins, Signal Transducing; C471855:Atf5 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D051155:Wnt1 Protein; D051176:beta Catenin