Theunissen, T. W. & Jaenisch, R. Mechanisms of gene regulation in human embryos and pluripotent stem cells. Development 144, 4496–4509 (2017).
Young, R. A. Control of the embryonic stem cell state. Cell 144, 940–954 (2011).
Bulut-Karslioglu, A. et al. The transcriptionally permissive chromatin state of embryonic stem cells is acutely tuned to translational output. Cell Stem Cell 22, 369–383.e8 (2018).
Iwafuchi-Doi, M. & Zaret, K. S. Cell fate control by pioneer transcription factors. Development 143, 1833–1837 (2016).
Freimer, J. W., Hu, T. J. & Blelloch, R. Decoupling the impact of microRNAs on translational repression versus RNA degradation in embryonic stem cells. eLife 7, e38014 (2018).
Atlasi, Y. et al. The translational landscape of ground state pluripotency. Nat. Commun. 11, 1617 (2020).
Tahmasebi, S., Khoutorsky, A., Mathews, M. B. & Sonenberg, N. Translation deregulation in human disease. Nat. Rev. Mol. Cell Biol. 19, 791–807 (2018).
Buszczak, M., Signer, R. A. J. & Morrison, S. J. Cellular differences in protein synthesis regulate tissue homeostasis. Cell 159, 242–251 (2014).
Gabut, M., Bourdelais, F. & Durand, S. Ribosome and translational control in stem cells. Cells 9, 497 (2020).
Hinnebusch, A. G., Ivanov, I. P. & Sonenberg, N. Translational control by 5′-untranslated regions of eukaryotic mRNAs. Science 352, 1413–1416 (2016).
Dever, T. E., Dinman, J. D. & Green, R. Translation elongation and recoding in eukaryotes. Cold Spring Harb. Perspect. Biol. 10, a032649 (2018).
Dever, T. E. & Green, R. The elongation, termination, and recycling phases of translation in eukaryotes. Cold Spring Harb. Perspect. Biol. 4, a013706 (2012).
Pisarev, A. V. et al. The role of ABCE1 in eukaryotic posttermination ribosomal recycling. Mol. Cell 37, 196–210 (2010).
Sampath, P. et al. A hierarchical network controls protein translation during murine embryonic stem cell self-renewal and differentiation. Cell Stem Cell 2, 448–460 (2008). Sampath et al. (2008) show for the first time that protein synthesis rates are low in mouse ESCs relative to differentiated cell types.
Fortier, S., MacRae, T., Bilodeau, M., Sargeant, T. & Sauvageau, G. Haploinsufficiency screen highlights two distinct groups of ribosomal protein genes essential for embryonic stem cell fate. Proc. Natl Acad. Sci. USA 112, 2127–2132 (2015).
Ingolia, N. T., Lareau, L. F. & Weissman, J. S. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147, 789–802 (2011). Ingolia et al. (2011) perform ribosome profiling for the first time in a stem cell lineage to reveal that the translational efficiency of many genes is upregulated during ESC differentiation through regulation by uORFs.
Blair, J. D., Hockemeyer, D., Doudna, J. A., Bateup, H. S. & Floor, S. N. Widespread translational remodeling during human neuronal differentiation. Cell Rep. 21, 2005–2016 (2017). Blair et al. (2017) perform transcript-isoform analysis that demonstrates that 3′ UTR regulation of translation increases as ESCs differentiate to neurons.
Notingher, I. et al. In situ spectral monitoring of mRNA translation in embryonic stem cells during differentiation in vitro. Anal. Chem. 76, 3185–3193 (2004).
Easley, C. A. 4th et al. mTOR-mediated activation of p70 S6K induces differentiation of pluripotent human embryonic stem cells. Cell. Reprogram. 12, 263–273 (2010).
Tan, S. M. et al. Divergent LIN28-mRNA associations result in translational suppression upon the initiation of differentiation. Nucleic Acids Res. 42, 7997–8007 (2014).
Signer, R. A. J., Magee, J. A., Salic, A. & Morrison, S. J. Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509, 49–54 (2014). This is one of the early studies to demonstrate that global protein synthesis rates are low in a stem cell lineage (HSCs) and that tight regulation of protein synthesis is required for HSC engraftment and prevention of cancer.
Jarzebowski, L. et al. Mouse adult hematopoietic stem cells actively synthesize ribosomal RNA. RNA 24, 1803–1812 (2018).
Signer, R. A. J. et al. The rate of protein synthesis in hematopoietic stem cells is limited partly by 4E-BPs. Genes Dev. 30, 1698–1703 (2016).
Blanco, S. et al. Stem cell function and stress response are controlled by protein synthesis. Nature 534, 335–340 (2016). Blanco et al. (2016) show that protein synthesis rates are low in epidermal hair follicle stem cells and that this regulation occurs through tRFs, which when dysregulated can contribute to tumorigenesis.
Liakath-Ali, K. et al. An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis. Nature 556, 376–380 (2018). Liakath-Ali et al. (2018) are the first to demonstrate the role of the ribosome rescue factor Pelota in an adult stem cell lineage.
Baser, A. et al. Onset of differentiation is post-transcriptionally controlled in adult neural stem cells. Nature 566, 100–104 (2019). Baser et al. (2019) demonstrate dynamic protein synthesis rates over the course of neural differentiation.
Zismanov, V. et al. Phosphorylation of eIF2α is a translational control mechanism regulating muscle stem cell quiescence and self-renewal. Cell Stem Cell 18, 79–90 (2016).
Sanchez, C. G. et al. Regulation of ribosome biogenesis and protein synthesis controls germline stem cell differentiation. Cell Stem Cell 18, 276–290 (2016).
Baßler, J. & Hurt, E. Eukaryotic ribosome assembly. Annu. Rev. Biochem. 88, 281–306 (2019).
Zaidi, S. K. et al. Expression of ribosomal RNA and protein genes in human embryonic stem cells is associated with the activating H3K4me3 histone mark. J. Cell. Physiol. 231, 2007–2013 (2016).
Cartwright, P. et al. LIF/STAT3 controls ES cell self-renewal and pluripotency by a Myc-dependent mechanism. Development 132, 885–896 (2005).
Watanabe-Susaki, K. et al. Biosynthesis of ribosomal RNA in nucleoli regulates pluripotency and differentiation ability of pluripotent stem cells. Stem Cell 32, 3099–3111 (2014).
Corsini, N. S. et al. Coordinated control of mRNA and rRNA processing controls embryonic stem cell pluripotency and differentiation. Cell Stem Cell 22, 543–558.e12 (2018). Corsini et al. (2018) reveal dynamic protein synthesis rates and RiBi as ESCs differentiate to EBs regulated by the factor HTATSF1.
Saez, I. et al. The E3 ubiquitin ligase UBR5 interacts with the H/ACA ribonucleoprotein complex and regulates ribosomal RNA biogenesis in embryonic stem cells. FEBS Lett. 594, 175–188 (2020).
Salomon-Kent, R. et al. New face for chromatin-related mesenchymal modulator: n-CHD9 localizes to nucleoli and interacts with ribosomal genes. J. Cell. Physiol. 230, 2270–2280 (2015).
van Riggelen, J., Yetil, A. & Felsher, D. W. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat. Rev. Cancer 10, 301–309 (2010).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Chappell, J. & Dalton, S. Roles for MYC in the establishment and maintenance of pluripotency. Cold Spring Harb. Perspect. Med. 3, a014381 (2013).
Herrlinger, S. et al. Lin28-mediated temporal promotion of protein synthesis is crucial for neural progenitor cell maintenance and brain development in mice. Development 146, dev173765 (2019).
Peng, S. et al. Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells. Stem Cells 29, 496–504 (2011).
Zhang, Q., Shalaby, N. A. & Buszczak, M. Changes in rRNA transcription influence proliferation and cell fate within a stem cell lineage. Science 343, 298–301 (2014).
Stedman, A. et al. Ribosome biogenesis dysfunction leads to p53-mediated apoptosis and goblet cell differentiation of mouse intestinal stem/progenitor cells. Cell Death Differ. 22, 1865–1876 (2015).
Le Bouteiller, M. et al. Notchless-dependent ribosome synthesis is required for the maintenance of adult hematopoietic stem cells. J. Exp. Med. 210, 2351–2369 (2013).
Cai, X. et al. Runx1 deficiency decreases ribosome biogenesis and confers stress resistance to hematopoietic stem and progenitor cells. Cell Stem Cell 17, 165–177 (2015).
Pereira, I. T. et al. Cardiomyogenic differentiation is fine-tuned by differential mRNA association with polysomes. BMC Genomics 20, 219 (2019).
de Klerk, E. et al. Assessing the translational landscape of myogenic differentiation by ribosome profiling. Nucleic Acids Res. 43, 4408–4428 (2015).
Marcon, B. H. et al. Downregulation of the protein synthesis machinery is a major regulatory event during early adipogenic differentiation of human adipose-derived stromal cells. Stem Cell Res. 25, 191–201 (2017).
Thomson, J. A. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020).
Thoreen, C. C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).
Hsieh, A. C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).
Morita, M. et al. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab. 18, 698–711 (2013).
Gandin, V. et al. nanoCAGE reveals 5′ UTR features that define specific modes of translation of functionally related MTOR-sensitive mRNAs. Genome Res. 26, 636–648 (2016).
Larsson, O. et al. Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc. Natl Acad. Sci. USA 109, 8977–8982 (2012).
Liu, X. et al. Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation. Nat. Cell Biol. 19, 626–638 (2017).
Hannan, K. M. et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol. Cell. Biol. 23, 8862–8877 (2003).
Mayer, C., Zhao, J., Yuan, X. & Grummt, I. mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev. 18, 423–434 (2004).
Michels, A. A. et al. mTORC1 directly phosphorylates and regulates human MAF1. Mol. Cell. Biol. 30, 3749–3757 (2010).
Moustafa-Kamal, M. et al. The mTORC1/S6K/PDCD4/eIF4A axis determines outcome of mitotic arrest. Cell Rep. 33, 108230 (2020).
Raught, B. et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 23, 1761–1769 (2004).
Wang, X. et al. Regulation of elongation factor 2 kinase by p90RSK1 and p70 S6 kinase. EMBO J. 20, 4370–4379 (2001).
Chauvin, C. et al. Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program. Oncogene 33, 474–483 (2014).
Meyuhas, O. Ribosomal protein S6 phosphorylation: four decades of research. Int. Rev. Cell Mol. Biol. 320, 41–73 (2015).
Raught, B. et al. Serum-stimulated, rapamycin-sensitive phosphorylation sites in the eukaryotic translation initiation factor 4GI. EMBO J. 19, 434–444 (2000).
Gangloff, Y.-G. et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol. Cell. Biol. 24, 9508–9516 (2004).
Hentges, K. E. et al. FRAP/mTOR is required for proliferation and patterning during embryonic development in the mouse. Proc. Natl Acad. Sci. USA 98, 13796–13801 (2001).
Murakami, M. et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol. Cell. Biol. 24, 6710–6718 (2004).
Jansova, D. et al. Regulation of 4E-BP1 activity in the mammalian oocyte. Cell Cycle 16, 927–939 (2017).
Guo, J. et al. Oocyte stage-specific effects of MTOR determine granulosa cell fate and oocyte quality in mice. Proc. Natl Acad. Sci. USA 115, E5326–E5333 (2018).
Bulut-Karslioglu, A. et al. Inhibition of mTOR induces a paused pluripotent state. Nature 540, 119–123 (2016).
Hartman, N. W. et al. mTORC1 targets the translational repressor 4E-BP2, but not S6 kinase 1/2, to regulate neural stem cell self-renewal in vivo. Cell Rep. 5, 433–444 (2013).
Arvidsson, A., Collin, T., Kirik, D., Kokaia, Z. & Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 8, 963–970 (2002).
Llorens-Bobadilla, E. et al. Single-cell transcriptomics reveals a population of dormant neural stem cells that become activated upon brain injury. Cell Stem Cell 17, 329–340 (2015).
Rodgers, J. T. et al. mTORC1 controls the adaptive transition of quiescent stem cells from G 0 to G Alert. Nature 510, 393–396 (2014).
Ding, X. et al. mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation. Nat. Commun. 7, 13226 (2016).
Ding, X. et al. Epidermal mammalian target of rapamycin complex 2 controls lipid synthesis and filaggrin processing in epidermal barrier formation. J. Allergy Clin. Immunol. 145, 283–300.e3 (2020).
He, J. et al. An elaborate regulation of mammalian target of rapamycin activity is required for somatic cell reprogramming induced by defined transcription factors. Stem Cell Dev. 21, 2630–2641 (2012).
Haller, S. et al. mTORC1 activation during repeated regeneration impairs somatic stem cell maintenance. Cell Stem Cell 21, 806–818.e5 (2017).
Fingar, D. C. et al. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol. Cell. Biol. 24, 200–216 (2004).
Fingar, D. C., Salama, S., Tsou, C., Harlow, E. & Blenis, J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 16, 1472–1487 (2002).
Cho, J. et al. LIN28A is a suppressor of ER-associated translation in embryonic stem cells. Cell 151, 765–777 (2012).
Magee, J. A. & Signer, R. A. J. Developmental stage-specific changes in protein synthesis differentially sensitize hematopoietic stem cells and erythroid progenitors to impaired ribosome biogenesis. Stem Cell Rep. 16, 20–28 (2021).
Copley, M. R. et al. The Lin28b–let-7–Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. Nat. Cell Biol. 15, 916–925 (2013).
Basak, A. et al. Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation. Nat. Genet. 52, 138–145 (2020).
Yuan, J., Nguyen, C. K., Liu, X., Kanellopoulou, C. & Muljo, S. A. Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science 335, 1195–1200 (2012).
Wang, S. et al. Transformation of the intestinal epithelium by the MSI2 RNA-binding protein. Nat. Commun. 6, 6517 (2015).
Park, S.-M. et al. Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program. J. Clin. Invest. 125, 1286–1298 (2015).
Vu, L. P. et al. Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells. Nat. Genet. 49, 866–875 (2017).
Ye, J. & Blelloch, R. Regulation of pluripotency by RNA binding proteins. Cell Stem Cell 15, 271–280 (2014).
Hung, S. S. C. et al. Repression of global protein synthesis by Eif1a-like genes that are expressed specifically in the two-cell embryos and the transient Zscan4-positive state of embryonic stem cells. DNA Res. 20, 391–402 (2013).
Buckley, S. M. et al. Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system. Cell Stem Cell 11, 783–798 (2012).
Chen, Z. Y., Wang, X., Zhou, Y., Offner, G. & Tseng, C.-C. Destabilization of Krüppel-like factor 4 protein in response to serum stimulation involves the ubiquitin-proteasome pathway. Cancer Res. 65, 10394–10400 (2005).
Vilchez, D. et al. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature 489, 304–308 (2012).
Koyuncu, S. et al. The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington’s disease patients. Nat. Commun. 9, 2886 (2018).
Noormohammadi, A. et al. Mechanisms of protein homeostasis (proteostasis) maintain stem cell identity in mammalian pluripotent stem cells. Cell. Mol. Life Sci. 75, 275–290 (2018).
Cui, C.-P. et al. Dynamic ubiquitylation of Sox2 regulates proteostasis and governs neural progenitor cell differentiation. Nat. Commun. 9, 4648 (2018).
Nguyen, A. T. et al. UBE2O remodels the proteome during terminal erythroid differentiation. Science 357, eaan0218 (2017).
Dez, C. & Tollervey, D. Ribosome synthesis meets the cell cycle. Curr. Opin. Microbiol. 7, 631–637 (2004).
Cheng, Z. et al. Small and large ribosomal subunit deficiencies lead to distinct gene expression signatures that reflect cellular growth rate. Mol. Cell 73, 36–47.e10 (2019).
Grollman, A. P. Cytotoxic inhibitors of protein synthesis. in Antineoplastic and Immunosuppressive Agents: Part II (eds Sartorelli, A. C. & Johns, D. G.) 554–570 (Springer, 1975).
Morgado-Palacin, L., Llanos, S. & Serrano, M. Ribosomal stress induces L11- and p53-dependent apoptosis in mouse pluripotent stem cells. Cell Cycle 11, 503–510 (2012).
Zambetti, N. A. et al. Deficiency of the ribosome biogenesis gene Sbds in hematopoietic stem and progenitor cells causes neutropenia in mice by attenuating lineage progression in myelocytes. Haematologica 100, 1285–1293 (2015).
Garçon, L. et al. Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients. Blood 122, 912–921 (2013).
Ludwig, L. S. et al. Altered translation of GATA1 in Diamond-Blackfan anemia. Nat. Med. 20, 748–753 (2014).
Khajuria, R. K. et al. Ribosome levels selectively regulate translation and lineage commitment in human hematopoiesis. Cell 173, 90–103.e19 (2018). Khajuria et al. (2018) demonstrate that ribosome levels are essential for proper stem cell differentiation and lineage commitment in the haematopoietic system.
Hesling, C., Oliveira, C. C., Castilho, B. A. & Zanchin, N. I. T. The Shwachman–Bodian–Diamond syndrome associated protein interacts with HsNip7 and its down-regulation affects gene expression at the transcriptional and translational levels. Exp. Cell Res. 313, 4180–4195 (2007).
Sinha, N. K. et al. EDF1 coordinates cellular responses to ribosome collisions. eLife 9, e58828 (2020).
Wu, C. C.-C., Peterson, A., Zinshteyn, B., Regot, S. & Green, R. Ribosome collisions trigger general stress responses to regulate cell fate. Cell 182, 404–416.e14 (2020).
Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).
Elkenani, M. et al. Pelota regulates epidermal differentiation by modulating BMP and PI3K/AKT signaling pathways. J. Invest. Dermatol. 136, 1664–1671 (2016).
de Klerk, E. & ’t Hoen, P. A. C. Alternative mRNA transcription, processing, and translation: insights from RNA sequencing. Trends Genet. 31, 128–139 (2015).
Wong, Q. W.-L. et al. Embryonic stem cells exhibit mRNA isoform specific translational regulation. PLoS ONE 11, e0143235 (2016).
Tahmasebi, S. et al. Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2. Proc. Natl Acad. Sci. USA 113, 12360–12367 (2016).
Tahmasebi, S. et al. Multifaceted regulation of somatic cell reprogramming by mRNA translational control. Cell Stem Cell 14, 606–616 (2014).
Svitkin, Y. V. et al. The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5′ secondary structure. RNA 7, 382–394 (2001).
Garcia-Garcia, C., Frieda, K. L., Feoktistova, K., Fraser, C. S. & Block, S. M. Factor-dependent processivity in human eIF4A DEAD-box helicase. Science 348, 1486–1488 (2015).
Rubio, C. A. et al. Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation. Genome Biol. 15, 476 (2014).
Wolfe, A. L. et al. RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer. Nature 513, 65–70 (2014). Wolfe et al. (2014) identify distinct translational signatures for eIF4A-regulated transcripts compared with mTOR/4E-BP/eIF4E-regulated transcripts in a cancer model system.
Nguyen, T. M. et al. FGFR1-activated translation of WNT pathway components with structured 5′ UTRs is vulnerable to inhibition of eif4a-dependent translation initiation. Cancer Res. 78, 4229–4240 (2018).
Kerr, C. L., Bol, G. M., Vesuna, F. & Raman, V. Targeting RNA helicase DDX3 in stem cell maintenance and teratoma formation. Genes Cancer 10, 11–20 (2019).
Lai, M.-C., Chang, W.-C., Shieh, S.-Y. & Tarn, W.-Y. DDX3 regulates cell growth through translational control of cyclin E1. Mol. Cell. Biol. 30, 5444–5453 (2010).
Soto-Rifo, R. et al. DEAD-box protein DDX3 associates with eIF4F to promote translation of selected mRNAs. EMBO J. 31, 3745–3756 (2012).
Truitt, M. L. et al. Differential requirements for eIF4E dose in normal development and cancer. Cell 162, 59–71 (2015).
Sen, N. D., Zhou, F., Harris, M. S., Ingolia, N. T. & Hinnebusch, A. G. eIF4B stimulates translation of long mRNAs with structured 5′ UTRs and low closed-loop potential but weak dependence on eIF4G. Proc. Natl Acad. Sci. USA 113, 10464–10472 (2016).
Sugiyama, H. et al. Nat1 promotes translation of specific proteins that induce differentiation of mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 114, 340–345 (2017).
Lee, A. S., Kranzusch, P. J., Doudna, J. A. & Cate, J. H. D. eIF3d is an mRNA cap-binding protein that is required for specialized translation initiation. Nature 536, 96–99 (2016).
de la Parra, C. et al. A widespread alternate form of cap-dependent mRNA translation initiation. Nat. Commun. 9, 3068 (2018).
Yang, G., Smibert, C. A., Kaplan, D. R. & Miller, F. D. An eIF4E1/4E-T complex determines the genesis of neurons from precursors by translationally repressing a proneurogenic transcription program. Neuron 84, 723–739 (2014).
Ingolia, N. T., Ghaemmaghami, S., Newman, J. R. S. & Weissman, J. S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009).
Bazzini, A. A. et al. Codon identity regulates mRNA stability and translation efficiency during the maternal-to-zygotic transition. EMBO J. 35, 2087–2103 (2016).
Morris, D. R. & Geballe, A. P. Upstream open reading frames as regulators of mRNA translation. Mol. Cell. Biol. 20, 8635–8642 (2000).
Starck, S. R. et al. Translation from the 5′untranslated region shapes the integrated stress response. Science 351, aad3867 (2016).
Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).
Hinnebusch, A. G. Translational regulation of yeast GCN4. A window on factors that control initiator-tRNA binding to the ribosome. J. Biol. Chem. 272, 21661–21664 (1997).
Vattem, K. M. & Wek, R. C. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl Acad. Sci. USA 101, 11269–11274 (2004).
Popa, A., Lebrigand, K., Barbry, P. & Waldmann, R. Pateamine A-sensitive ribosome profiling reveals the scope of translation in mouse embryonic stem cells. BMC Genomics 17, 52 (2016).
Fujii, K., Shi, Z., Zhulyn, O., Denans, N. & Barna, M. Pervasive translational regulation of the cell signalling circuitry underlies mammalian development. Nat. Commun. 8, 14443 (2017).
Paolini, N. A. et al. Ribosome profiling uncovers selective mRNA translation associated with eIF2 phosphorylation in erythroid progenitors. PLoS ONE 13, e0193790 (2018).
Friend, K., Brooks, H. A., Propson, N. E., Thomson, J. A. & Kimble, J. Embryonic stem cell growth factors regulate eIF2α phosphorylation. PLoS ONE 10, e0139076 (2015).
Chen, J. et al. Pervasive functional translation of noncanonical human open reading frames. Science 367, 1140–1146 (2020).
Mayr, C. Regulation by 3′-untranslated regions. Annu. Rev. Genet. 51, 171–194 (2017).
Floor, S. N. & Doudna, J. A. Tunable protein synthesis by transcript isoforms in human cells. eLife 5, e10921 (2016).
Sandberg, R., Neilson, J. R., Sarma, A., Sharp, P. A. & Burge, C. B. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 1643–1647 (2008).
Mayr, C. & Bartel, D. P. Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673–684 (2009).
Ji, Z., Lee, J. Y., Pan, Z., Jiang, B. & Tian, B. Progressive lengthening of 3′ untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. Proc. Natl Acad. Sci. USA 106, 7028–7033 (2009).
Göpferich, M. et al. Single cell 3′UTR analysis identifies changes in alternative polyadenylation throughout neuronal differentiation and in autism. Preprint at bioRxiv https://doi.org/10.1101/2020.08.12.247627 (2020).
Wang, Y., Arribas-Layton, M., Chen, Y., Lykke-Andersen, J. & Sen, G. L. DDX6 orchestrates mammalian progenitor function through the mRNA degradation and translation pathways. Mol. Cell 60, 118–130 (2015).
Boutet, S. C. et al. Alternative polyadenylation mediates microRNA regulation of muscle stem cell function. Cell Stem Cell 10, 327–336 (2012).
Spangenberg, L. et al. Polysome profiling shows extensive posttranscriptional regulation during human adipocyte stem cell differentiation into adipocytes. Stem Cell Res. 11, 902–912 (2013).
Lodish, H. F. Model for the regulation of mRNA translation applied to haemoglobin synthesis. Nature 251, 385–388 (1974).
Mills, E. W. & Green, R. Ribosomopathies: there’s strength in numbers. Science 358, eaan2755 (2017).
Chennupati, V. et al. Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation. J. Clin. Invest. 128, 1597–1614 (2018).
Popis, M. C., Blanco, S. & Frye, M. Posttranscriptional methylation of transfer and ribosomal RNA in stress response pathways, cell differentiation, and cancer. Curr. Opin. Oncol. 28, 65–71 (2016).
Bornelöv, S., Selmi, T., Flad, S., Dietmann, S. & Frye, M. Codon usage optimization in pluripotent embryonic stem cells. Genome Biol. 20, 119 (2019).
Presnyak, V. et al. Codon optimality is a major determinant of mRNA stability. Cell 160, 1111–1124 (2015).
Radhakrishnan, A. et al. The DEAD-box protein Dhh1p couples mRNA decay and translation by monitoring codon optimality. Cell 167, 122–132.e9 (2016).
Goncalves, K. A. et al. Angiogenin promotes hematopoietic regeneration by dichotomously regulating quiescence of stem and progenitor cells. Cell 166, 894–906 (2016).
Guzzi, N. et al. Pseudouridylation of tRNA-derived fragments steers translational control in stem cells. Cell 173, 1204–1216.e26 (2018). Guzzi et al. (2018) show that tRF generation in ESCs contributes to the inhibition of global protein synthesis.
Gingold, H. et al. A dual program for translation regulation in cellular proliferation and differentiation. Cell 158, 1281–1292 (2014).
Lin, S. et al. Mettl1/Wdr4-mediated m7G tRNA methylome is required for normal mRNA translation and embryonic stem cell self-renewal and differentiation. Mol. Cell 71, 244–255.e5 (2018).
Tuorto, F. et al. The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis. EMBO J. 34, 2350–2362 (2015).
Su, Z., Kuscu, C., Malik, A., Shibata, E. & Dutta, A. Angiogenin generates specific stress-induced tRNA halves and is not involved in tRF-3-mediated gene silencing. J. Biol. Chem. 294, 16930–16941 (2019).
Yamasaki, S., Ivanov, P., Hu, G.-F. & Anderson, P. Angiogenin cleaves tRNA and promotes stress-induced translational repression. J. Cell Biol. 185, 35–42 (2009).
Ivanov, P., Emara, M. M., Villen, J., Gygi, S. P. & Anderson, P. Angiogenin-induced tRNA fragments inhibit translation initiation. Mol. Cell 43, 613–623 (2011).
Blanco, S. et al. The RNA-methyltransferase Misu (NSun2) poises epidermal stem cells to differentiate. PLoS Genet. 7, e1002403 (2011).
Hussain, S. et al. The mouse cytosine-5 RNA methyltransferase NSun2 is a component of the chromatoid body and required for testis differentiation. Mol. Cell. Biol. 33, 1561–1570 (2013).
Kahvejian, A., Roy, G. & Sonenberg, N. The mRNA closed-loop model: the function of PABP and PABP-interacting proteins in mRNA translation. Cold Spring Harb. Symp. Quant. Biol. 66, 293–300 (2001).
Pinkard, O., McFarland, S., Sweet, T. & Coller, J. Quantitative tRNA-sequencing uncovers metazoan tissue-specific tRNA regulation. Nat. Commun. 11, 4104 (2020).
Xu, Y. & Ruggero, D. The Role of translation control in tumorigenesis and its therapeutic implications. Annu. Rev. Cancer Biol. 4, 437–457 (2020).
Robichaud, N., Sonenberg, N., Ruggero, D. & Schneider, R. J. Translational control in cancer. Cold Spring Harb. Perspect. Biol. 11, 254–266 (2019).
Morral, C. et al. Zonation of ribosomal DNA transcription defines a stem cell hierarchy in colorectal cancer. Cell Stem Cell 26, 845–861.e12 (2020).
Chen, L. et al. Circ-MALAT1 functions as both an mRNA translation brake and a microRNA sponge to promote self-renewal of hepatocellular cancer stem cells. Adv. Sci. 7, 1900949 (2020).
Meacham, C. E. & Morrison, S. J. Tumour heterogeneity and cancer cell plasticity. Nature 501, 328–337 (2013).
Lim, S. et al. Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc. Natl Acad. Sci. USA 110, E2298–E2307 (2013).
Jögi, A., Vaapil, M., Johansson, M. & Påhlman, S. Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors. Ups. J. Med. Sci. 117, 217–224 (2012).
de Thé, H. Differentiation therapy revisited. Nat. Rev. Cancer 18, 117–127 (2018).
Enane, F. O., Saunthararajah, Y. & Korc, M. Differentiation therapy and the mechanisms that terminate cancer cell proliferation without harming normal cells. Cell Death Dis. 9, 912 (2018).
Sendoel, A. et al. Translation from unconventional 5′ start sites drives tumour initiation. Nature 541, 494–499 (2017). Sendoel et al. (2017) show that SOX2 induction in the embryonic epidermis drives tumorigenesis through inhibition of eIF2.
Zhang, S., Xiong, X. & Sun, Y. Functional characterization of SOX2 as an anticancer target. Signal. Transduct. Target. Ther. 5, 135 (2020).
Nguyen, H. G. et al. Development of a stress response therapy targeting aggressive prostate cancer. Sci. Transl. Med. 10, eaar2036 (2018).
Manier, S. et al. Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma. Sci. Transl. Med. 9, eaal2668 (2017).
Lazaris-Karatzas, A., Montine, K. S. & Sonenberg, N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′cap. Nature 345, 544–547 (1990).
Rosenwald, I. B., Lazaris-Karatzas, A., Sonenberg, N. & Schmidt, E. V. Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol. Cell. Biol. 13, 7358–7363 (1993).
Suresh, S. et al. eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer. Nat. Cancer 1, 533–545 (2020).
Xu, Y. et al. Translation control of the immune checkpoint in cancer and its therapeutic targeting. Nat. Med. 25, 301–311 (2019).
Vazquez-Arango, P. et al. Variant U1 snRNAs are implicated in human pluripotent stem cell maintenance and neuromuscular disease. Nucleic Acids Res. 44, 10960–10973 (2016).
Oh, J.-M. et al. U1 snRNP regulates cancer cell migration and invasion in vitro. Nat. Commun. 11, 1 (2020).
Fares, J., Fares, M. Y., Khachfe, H. H., Salhab, H. A. & Fares, Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal. Transduct. Target. Ther. 5, 28 (2020).
Yuan, S., Norgard, R. J. & Stanger, B. Z. Cellular plasticity in cancer. Cancer Discov. 9, 837–851 (2019).
Feng, Y.-X. et al. Epithelial-to-mesenchymal transition activates PERK–eIF2α and sensitizes cells to endoplasmic reticulum stress. Cancer Discov. 4, 702–715 (2014).
Goodarzi, H. et al. Modulated expression of specific tRNAs drives gene expression and cancer progression. Cell 165, 1416–1427 (2016).
Ebright, R. Y. et al. Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis. Science 367, 1468–1473 (2020).
van Heesch, S. et al. The translational landscape of the human heart. Cell 178, 242–260.e29 (2019).
Guttman, M. et al. lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477, 295–300 (2011).
Gong, C. et al. A long non-coding RNA, LncMyoD, regulates skeletal muscle differentiation by blocking IMP2-mediated mRNA translation. Dev. Cell 34, 181–191 (2015).
Batista, P. J. et al. m6A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15, 707–719 (2014).
Vu, L. P. et al. The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat. Med. 23, 1369–1376 (2017).
Lin, S., Choe, J., Du, P., Triboulet, R. & Gregory, R. I. The m6A methyltransferase METTL3 promotes translation in human cancer cells. Mol. Cell 62, 335–345 (2016).
Shi, H. et al. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res. 27, 315–328 (2017).
Choe, J. et al. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature 561, 556–560 (2018).
Ishimura, R., Nagy, G., Dotu, I., Chuang, J. H. & Ackerman, S. L. Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation. eLife 5, e14295 (2016).
Mahdessian, D. et al. Spatiotemporal dissection of the cell cycle with single-cell proteogenomics. Nature 590, 649–654 (2021).
Regot, S., Hughey, J. J., Bajar, B. T., Carrasco, S. & Covert, M. W. High-sensitivity measurements of multiple kinase activities in live single cells. Cell 157, 1724–1734 (2014).
Aikin, T. J., Peterson, A. F., Pokrass, M. J., Clark, H. R. & Regot, S. MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression. eLife 9, e60541 (2020).
Lewandowski, B. et al. Sequence-specific peptide synthesis by an artificial small-molecule machine. Science 339, 189–193 (2013).
O’Connell, A. E. et al. Mammalian Hbs1L deficiency causes congenital anomalies and developmental delay associated with Pelota depletion and 80S monosome accumulation. PLoS Genet. 15, e1007917 (2019).
Posfai, E. et al. Evaluating totipotency using criteria of increasing stringency. Nat. Cell Biol. 23, 49–60 (2021).
De Paepe, C., Krivega, M., Cauffman, G., Geens, M. & Van de Velde, H. Totipotency and lineage segregation in the human embryo. Mol. Hum. Reprod. 20, 599–618 (2014).
Davidson, K. C., Mason, E. A. & Pera, M. F. The pluripotent state in mouse and human. Development 142, 3090–3099 (2015).
Weinberger, L., Ayyash, M., Novershtern, N. & Hanna, J. H. Dynamic stem cell states: naive to primed pluripotency in rodents and humans. Nat. Rev. Mol. Cell Biol. 17, 155–169 (2016).
Neagu, A. et al. In vitro capture and characterization of embryonic rosette-stage pluripotency between naive and primed states. Nat. Cell Biol. 22, 534–545 (2020).
Ying, Q.-L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008).
Huang, J. et al. Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J. Clin. Invest. 119, 3519–3529 (2009).
Mendoza, M. C., Er, E. E. & Blenis, J. The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends Biochem. Sci. 36, 320–328 (2011).
Hu, Z. et al. Transient inhibition of mTOR in human pluripotent stem cells enables robust formation of mouse-human chimeric embryos. Sci. Adv. 6, eaaz0298 (2020).
Scognamiglio, R. et al. Myc depletion induces a pluripotent dormant state mimicking diapause. Cell 164, 668–680 (2016).
Marks, H. et al. The transcriptional and epigenomic foundations of ground state pluripotency. Cell 149, 590–604 (2012).
Pandolfini, L. et al. RISC-mediated control of selected chromatin regulators stabilizes ground state pluripotency of mouse embryonic stem cells. Genome Biol. 17, 94 (2016).
Lane, S. W., Williams, D. A. & Watt, F. M. Modulating the stem cell niche for tissue regeneration. Nat. Biotechnol. 32, 795–803 (2014).
Vining, K. H. & Mooney, D. J. Mechanical forces direct stem cell behaviour in development and regeneration. Nat. Rev. Mol. Cell Biol. 18, 728–742 (2017).
Watt, F. M. & Huck, W. T. S. Role of the extracellular matrix in regulating stem cell fate. Nat. Rev. Mol. Cell Biol. 14, 467–473 (2013).
Fletcher, D. A. & Mullins, R. D. Cell mechanics and the cytoskeleton. Nature 463, 485–492 (2010).
Gross, S. R. & Kinzy, T. G. Improper organization of the actin cytoskeleton affects protein synthesis at initiation. Mol. Cell. Biol. 27, 1974–1989 (2007).
Stapulionis, R., Kolli, S. & Deutscher, M. P. Efficient mammalian protein synthesis requires an intact F-actin system. J. Biol. Chem. 272, 24980–24986 (1997).
Silva, R. C., Sattlegger, E. & Castilho, B. A. Perturbations in actin dynamics reconfigure protein complexes that modulate GCN2 activity and promote an eIF2 response. J. Cell Sci. 129, 4521–4533 (2016).
Martin, K. C. & Ephrussi, A. mRNA localization: gene expression in the spatial dimension. Cell 136, 719–730 (2009).
Kim, S., Wong, P. & Coulombe, P. A. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 441, 362–365 (2006).
Coulombe, P. A. & Wong, P. Cytoplasmic intermediate filaments revealed as dynamic and multipurpose scaffolds. Nat. Cell Biol. 6, 699–706 (2004).
Kim, S. & Coulombe, P. A. Emerging role for the cytoskeleton as an organizer and regulator of translation. Nat. Rev. Mol. Cell Biol. 11, 75–81 (2010).
Chicurel, M. E., Singer, R. H., Meyer, C. J. & Ingber, D. E. Integrin binding and mechanical tension induce movement of mRNA and ribosomes to focal adhesions. Nature 392, 730–733 (1998).
Chung, J. & Kim, T. H. Integrin-dependent translational control: implication in cancer progression. Microsc. Res. Tech. 71, 380–386 (2008).
Willett, M., Pollard, H. J., Vlasak, M. & Morley, S. J. Localization of ribosomes and translation initiation factors to talin/β3-integrin-enriched adhesion complexes in spreading and migrating mammalian cells. Biol. Cell 102, 265–276 (2010).
Lian, I. et al. The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Dev. 24, 1106–1118 (2010).
Walko, G. et al. A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells. Nat. Commun. 8, 14744 (2017).
Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).
Goodman, C. A. et al. Yes-associated protein is up-regulated by mechanical overload and is sufficient to induce skeletal muscle hypertrophy. FEBS Lett. 589, 1491–1497 (2015).
Judson, R. N. et al. The Hippo pathway member Yap plays a key role in influencing fate decisions in muscle satellite cells. J. Cell Sci. 125, 6009–6019 (2012).
Watt, K. I. et al. The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size. Nat. Commun. 6, 6048 (2015).
Park, Y.-Y. et al. Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma. Hepatology 63, 159–172 (2016).
Hansen, C. G., Ng, Y. L. D., Lam, W.-L. M., Plouffe, S. W. & Guan, K.-L. The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1. Cell Res. 25, 1299–1313 (2015).
Tumaneng, K. et al. YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29. Nat. Cell Biol. 14, 1322–1329 (2012).
Ruwhof, C. & van der Laarse, A. Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways. Cardiovasc. Res. 47, 23–37 (2000).
Sherwood, D. J. et al. Differential regulation of MAP kinase, p70S6K, and Akt by contraction and insulin in rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 276, E870–E878 (1999).
Sakamoto, K., Hirshman, M. F., Aschenbach, W. G. & Goodyear, L. J. Contraction regulation of Akt in rat skeletal muscle. J. Biol. Chem. 277, 11910–11917 (2002).
Sugimoto, A. et al. Piezo type mechanosensitive ion channel component 1 functions as a regulator of the cell fate determination of mesenchymal stem cells. Sci. Rep. 7, 17696 (2017).
Del Mármol, J. I., Touhara, K. K., Croft, G. & MacKinnon, R. Piezo1 forms a slowly-inactivating mechanosensory channel in mouse embryonic stem cells. eLife 7, e33149 (2018).
Pathak, M. M. et al. Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells. Proc. Natl Acad. Sci. USA 111, 16148–16153 (2014).
Wang, L. et al. Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk. Nat. Commun. 11, 282 (2020).
Han, Y. et al. Mechanosensitive ion channel Piezo1 promotes prostate cancer development through the activation of the Akt/mTOR pathway and acceleration of cell cycle. Int. J. Oncol. 55, 629–644 (2019).