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Transcriptome-wide analysis of mRNA translation and associated post-transcriptional regulatory mechanisms following neuronal membrane depolarisation

ABSTRACT: Here, we employed ribosome profiling to explore global changes in mRNA translational status in neuronally differentiated neuroblast cultures at several time-points after whole cell depolarisation, and compared this to steady-state mRNA levels. Immediately after depolarisation, genes with known function at the synapse were subjected to a surge of translational activity without corresponding changes in mRNA levels. At later time-points, however, these changes became synchronised, suggesting there are different layers of post-transcriptional regulation which are temporally separated but become coordinated over time. Sequencing of small RNAs additionally revealed that changes in microRNA (miRNA) and tRNA-derived small RNA fragments (tRFs) coincided with this early post-transcriptional disparity, however these molecules exhibited strongest association with the remodelling of mRNA steady-state levels. Transcripts displaying high levels of translational dynamics relative to underlying mRNA levels were characterised by more intrinsic features, including mRNA length, GC content, secondary structure and motifs for RNA binding proteins. These data suggest that activity-associated neuronal translation is initially regulated independently of mRNA levels, wherein transcript features contribute to modulation of mRNA translatability, while miRNA and tRFs fine-tune mRNA levels.

ORGANISM(S): Homo sapiens

PROVIDER: GSE155727 | GEO | 2020/09/25

REPOSITORIES: GEO

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Project description:Eukaryotic cells are constantly challenged by the presence of reactive oxygen species, which play an important role in aging and human disease progression. In particular, acute oxidative stress can lead to extensive damage to cellular DNA, proteins, and lipids and can trigger a response that remodels the transcriptional and translational state of the cell. Although a number of previous studies have profiled the relative changes in mRNA and protein and more studies revealing the dynamics of transcription and translation in response to stress are starting to emerge, a quantitative view of this response has been lacking. Here, we have applied quantitative methods to characterize the time dynamics of mRNA and protein levels in the oxidative stress response of the fission yeast Schizosaccharomyces pombe, which has allowed us to perform dynamic modeling of responsive genes in units of copies per cell. Analysis of the resulting time dynamics provided a new genome-wide view of the scale, timing and rates of transcription and translation in the transient response. The majority of dynamic genes were observed to be responsive in their mRNA or protein levels alone implying extensive translational regulation. Nevertheless, modeling of genes with responsive mRNA and protein levels showed that protein levels could, in a majority of these cases, be accurately predicted with constant translation and decay rates while a minority benefited from explicit translation delay parameters. A number of independent features, e.g. measures of codon bias, ribosome occupancy, etc., were found to be less correlated to maximally perturbed protein levels than steady-state levels. Codon bias measures were more correlated than mRNA levels to quantitative protein levels at both perturbed and un-perturbed states. Measures of translation activity, on the other hand, were only significantly correlated at steady state. In total 32 samples: 11 for stressed time series R1, 11 for stressed time series R2, 5 for control time series C1 and 5 for control time series C2

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Transcriptome-wide analysis of mRNA translation and associated post-transcriptional regulatory mechanisms following neuronal membrane depolarisation

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