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Codon usage optimization in pluripotent embryonic stem cells [RNA-seq]

ABSTRACT: 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 on regulating cell state-specific expression programs is currently debated. Here, we asked whether the gene expression program in the well-defined cell states of self-renewal and differentiation in embryonic stem cells is driven by optimized codon usage. Using ribosome and transcriptome profiling, we identified distinct codon signatures for human self-renewing and differentiating embryonic stem cells. One driver for the cell state-specific codon bias was the genomic GC-content of the differentially expressed genes and thus, determined by transcription rather than translation. However, by measuring the codon frequencies at the ribosome’s active sites interacting with transfer RNAs (tRNA), we discovered that the wobble position tRNA modification inosine strongly influenced the codon optimization in self-renewing embryonic stem cells. This effect was conserved in mice and independent of the differentiation stimulus. In summary, we newly reveal how translational mechanisms based on RNA modifications can shape optimized codon usage in embryonic stem cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112085 | GEO | 2019/05/17

REPOSITORIES: GEO

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Project description:Artemisinin (ART)-resistant Plasmodium falciparum (Pf) threatens global malaria control. Resistance, driven by mutations in Pfk13, is multifaceted but quiescence plays a central role. Epigenetic regulation may contribute, given that only a percentage of parasites survive a pulse of the active drug metabolite dihydroartemisinin (DHA). The identities or roles of these epigenetic factors, however, have yet to be identified. tRNA modifications are a conserved epigenetic translational control mechanism, whereby cellular stress leads to modification reprogramming and codon-biased translation. Here we use liquid chromatography-mass spectrometry to profile tRNA modifications in ring-stage ART-sensitive (ART-S) Dd2 and ART-resistant (ART-R) Dd2PfK13_R539T before and after drug pulse. ART-R parasites differentially reprogram their tRNA modification profiles in response to DHA, specifically by mcm5s2U hypomodification of tRNAs. Proteomic and subsequent codon usage analysis revealed that the ART-R parasite proteome displays codon bias, uncovering a new layer of proteomic regulation in drug-resistant parasites. A subset of these proteins were not transcriptionally regulated, suggesting codon-bias translation. Upregulated proteins were enriched for LysAAA, HisCAT and AspGAT and downregulated proteins were enriched for their cognate codons (LysAAG, HisCAC and AspGAC). PfK13 and its interacting partner BIP were among the codon-controlled upregulated proteins. Interestingly, mcm5s2U occurs on the U34 of LysAAA/AAG codons to regulate translational fidelity, providing a mechanistic link between tRNA modification and proteomic data. Transcriptomics revealed enrichment of wobble-base tRNA modification in ART-R parasites post-ART treatment. An anhydrotetracycline-regulated conditional knockdown (cKD) of the terminal s2U methyltransferase, PfMnmA, displayed increased ART survival, signifying that hypomodification plays a critical role in the ART-R parasite response to DHA. cKD parasites also had altered responses to proteotoxic and mitochondrial antimalarials, uncovering overlaps between epigenetic stress response pathways. This work describes a novel epigenetic pathway via tRNA s2U reprogramming that ART-R parasites may use to help survive ART-induced stress.

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Codon usage optimization in pluripotent embryonic stem cells [RNA-seq]

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