Codon usage optimization in pluripotent embryonic stem cells.
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Borneloev, S., Selmi, T., Flad, S., Dietmann, S., & Frye, M. (2019). Codon usage optimization in pluripotent embryonic stem cells.. Genome biology, 20 (1), 119. https://doi.org/10.1186/s13059-019-1726-z
Background: The uneven use of synonymous codons in the transcriptome regulates the efficiency and fidelity of protein translation rates. Yet, the importance of this codon bias in regulating cell state-specific expression programs is currently debated. Here, we ask whether different codon usage controls gene expression programs in self-renewing and differentiating embryonic stem cells. Results: Using ribosome and transcriptome profiling, we identify distinct codon signatures during human embryonic stem cell differentiation. We find that cell state-specific codon bias is determined by the GC-content of differentially expressed genes. By measuring the codon frequencies at the ribosome active sites interacting with transfer RNAs (tRNA), we further discover that self-renewing cells optimize translation of codons that depend on the inosine tRNA modification in the anti-codon wobble position. Accordingly, inosine levels are highest in human pluripotent embryonic stem cells. This effect is conserved in mice and is independent of the differentiation stimulus. Conclusions: We show that GC-content influences cell state-specific mRNA levels, and we reveal how translational mechanisms based on tRNA modifications change codon usage in embryonic stem cells.
Animals, Humans, Codon, RNA, Transfer, Protein Biosynthesis, Base Composition, Embryonic Stem Cells, Cell Self Renewal
This work was funded by Cancer Research UK (CR-UK) and the Medical Research Council (MRC). Parts of this research in Michaela Frye's laboratory was supported by core funding from Wellcome and MRC to the Wellcome-MRC Cambridge Stem Cell Institute.
Cancer Research UK (15181)
MEDICAL RESEARCH COUNCIL (MR/M01939X/1)
Embargo Lift Date
External DOI: https://doi.org/10.1186/s13059-019-1726-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293313
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