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Post-transcriptional regulation across human tissues

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  • Alexander Franks
  • Edoardo Airoldi
  • Nikolai Slavov

Abstract

Transcriptional and post-transcriptional regulation shape tissue-type-specific proteomes, but their relative contributions remain contested. Estimates of the factors determining protein levels in human tissues do not distinguish between (i) the factors determining the variability between the abundances of different proteins, i.e., mean-level-variability and, (ii) the factors determining the physiological variability of the same protein across different tissue types, i.e., across-tissues variability. We sought to estimate the contribution of transcript levels to these two orthogonal sources of variability, and found that scaled mRNA levels can account for most of the mean-level-variability but not necessarily for across-tissues variability. The reliable quantification of the latter estimate is limited by substantial measurement noise. However, protein-to-mRNA ratios exhibit substantial across-tissues variability that is functionally concerted and reproducible across different datasets, suggesting extensive post-transcriptional regulation. These results caution against estimating protein fold-changes from mRNA fold-changes between different cell-types, and highlight the contribution of post-transcriptional regulation to shaping tissue-type-specific proteomes.Author Summary: The identity of human tissues depends on their protein levels. Are tissue protein levels set largely by corresponding mRNA levels or by other (post-transcriptional) regulatory mechanisms? We revisit this question based on statistical analysis of mRNA and protein levels measured across human tissues. We find that for any one gene, its protein levels across tissues are poorly predicted by its mRNA levels, suggesting tissue-specific post-transcriptional regulation. In contrast, the overall protein levels are well predicted by scaled mRNA levels. We show how these speciously contradictory findings are consistent with each other and represent the two sides of Simpson’s paradox.

Suggested Citation

  • Alexander Franks & Edoardo Airoldi & Nikolai Slavov, 2017. "Post-transcriptional regulation across human tissues," PLOS Computational Biology, Public Library of Science, vol. 13(5), pages 1-20, May.
  • Handle: RePEc:plo:pcbi00:1005535
    DOI: 10.1371/journal.pcbi.1005535
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    References listed on IDEAS

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    1. Gábor Csárdi & Alexander Franks & David S Choi & Edoardo M Airoldi & D Allan Drummond, 2015. "Accounting for Experimental Noise Reveals That mRNA Levels, Amplified by Post-Transcriptional Processes, Largely Determine Steady-State Protein Levels in Yeast," PLOS Genetics, Public Library of Science, vol. 11(5), pages 1-32, May.
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    Cited by:

    1. Zahra Z. Farahbakhsh & Katherine M. Holleran & Jonathon P. Sens & Steve C. Fordahl & Madelyn I. Mauterer & Alberto J. López & Verginia C. Cuzon Carlson & Drew D. Kiraly & Kathleen A. Grant & Sara R. J, 2025. "Synchrony between midbrain gene transcription and dopamine terminal regulation is modulated by chronic alcohol drinking," Nature Communications, Nature, vol. 16(1), pages 1-17, December.

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