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      Ribosome and Translational Control in Stem Cells

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          Abstract

          Embryonic stem cells (ESCs) and adult stem cells (ASCs) possess the remarkable capacity to self-renew while remaining poised to differentiate into multiple progenies in the context of a rapidly developing embryo or in steady-state tissues, respectively. This ability is controlled by complex genetic programs, which are dynamically orchestrated at different steps of gene expression, including chromatin remodeling, mRNA transcription, processing, and stability. In addition to maintaining stem cell homeostasis, these molecular processes need to be rapidly rewired to coordinate complex physiological modifications required to redirect cell fate in response to environmental clues, such as differentiation signals or tissue injuries. Although chromatin remodeling and mRNA expression have been extensively studied in stem cells, accumulating evidence suggests that stem cell transcriptomes and proteomes are poorly correlated and that stem cell properties require finely tuned protein synthesis. In addition, many studies have shown that the biogenesis of the translation machinery, the ribosome, is decisive for sustaining ESC and ASC properties. Therefore, these observations emphasize the importance of translational control in stem cell homeostasis and fate decisions. In this review, we will provide the most recent literature describing how ribosome biogenesis and translational control regulate stem cell functions and are crucial for accommodating proteome remodeling in response to changes in stem cell fate.

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          Most cited references132

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          Translational control by 5'-untranslated regions of eukaryotic mRNAs.

          The eukaryotic 5' untranslated region (UTR) is critical for ribosome recruitment to the messenger RNA (mRNA) and start codon choice and plays a major role in the control of translation efficiency and shaping the cellular proteome. The ribosomal initiation complex is assembled on the mRNA via a cap-dependent or cap-independent mechanism. We describe various mechanisms controlling ribosome scanning and initiation codon selection by 5' upstream open reading frames, translation initiation factors, and primary and secondary structures of the 5'UTR, including particular sequence motifs. We also discuss translational control via phosphorylation of eukaryotic initiation factor 2, which is implicated in learning and memory, neurodegenerative diseases, and cancer.
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            Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans.

            Upstream ORFs (uORFs) are mRNA elements defined by a start codon in the 5' UTR that is out-of-frame with the main coding sequence. Although uORFs are present in approximately half of human and mouse transcripts, no study has investigated their global impact on protein expression. Here, we report that uORFs correlate with significantly reduced protein expression of the downstream ORF, based on analysis of 11,649 matched mRNA and protein measurements from 4 published mammalian studies. Using reporter constructs to test 25 selected uORFs, we estimate that uORFs typically reduce protein expression by 30-80%, with a modest impact on mRNA levels. We additionally identify polymorphisms that alter uORF presence in 509 human genes. Finally, we report that 5 uORF-altering mutations, detected within genes previously linked to human diseases, dramatically silence expression of the downstream protein. Together, our results suggest that uORFs influence the protein expression of thousands of mammalian genes and that variation in these elements can influence human phenotype and disease.
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              Haematopoietic stem cells require a highly regulated protein synthesis rate

              Many aspects of cellular physiology remain unstudied in somatic stem cells. For example, there are almost no data on protein synthesis in any somatic stem cell. We found that the amount of protein synthesized per hour in haematopoietic stem cells (HSCs) in vivo was lower than in most other haematopoietic cells, even if we controlled for differences in cell cycle status or forced HSCs to undergo self-renewing divisions. Reduced ribosome function in Rpl24 Bst/+ mice further reduced protein synthesis in HSCs and impaired HSC function. Pten deletion increased protein synthesis in HSCs but also reduced HSC function. Rpl24Bst/+ cell-autonomously rescued the effects of Pten deletion in HSCs, blocking the increase in protein synthesis, restoring HSC function, and delaying leukaemogenesis. Pten deficiency thus depletes HSCs and promotes leukaemia partly by increasing protein synthesis. Either increased or decreased protein synthesis impairs HSC function.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                21 February 2020
                February 2020
                : 9
                : 2
                : 497
                Affiliations
                [1 ]Equipe ‘Transcriptome Diversity in Stem Cells’, Cancer Cell Plasticity Department, INSERM 1052, CNRS 5286, Cancer Research Center of Lyon, Centre Léon Bérard, 69008 Lyon, France fleur.bourdelais@ 123456gmail.com (F.B.)
                [2 ]Université Claude Bernard Lyon 1, 69100 Villeurbanne, France
                Author notes
                [* ]Correspondence: sebastien.durand@ 123456inserm.fr ; Tel.: +33-469-856-092
                Author information
                https://orcid.org/0000-0001-7343-5361
                https://orcid.org/0000-0002-9960-9099
                Article
                cells-09-00497
                10.3390/cells9020497
                7072746
                32098201
                def63d91-fc31-4810-bd72-aa2e10031815
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 January 2020
                : 17 February 2020
                Categories
                Review

                ribosomes,stem cells,translational regulation,ribosomal proteins,rrna modifications,ribosome biogenesis,specialized ribosomes

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