Abstract
Cells respond to their environment by modulating protein levels through mRNA transcription and post-transcriptional control. Modest observed correlations between global steady-state mRNA and protein measurements have been interpreted as evidence that mRNA levels determine roughly 40% of the variation in protein levels, indicating dominant post-transcriptional effects. However, the techniques underlying these conclusions, such as correlation and regression, yield biased results when data are noisy, missing systematically, and collinear---properties of mRNA and protein measurements---which motivated us to revisit this subject. Noise-robust analyses of 24 studies of budding yeast reveal that mRNA levels explain more than 85% of the variation in steady-state protein levels. Protein levels are not proportional to mRNA levels, but rise much more rapidly. Regulation of translation suffices to explain this nonlinear effect, revealing post-transcriptional amplification of, rather than competition with, transcriptional signals. These results substantially revise widely credited models of protein-level regulation, and introduce multiple noise-aware approaches essential for proper analysis of many biological phenomena.
Highlights
Cellular protein levels reflect the balance of mRNA levels, protein production by translation initiation and completion, and protein removal by degradation, secretion, and dilution due to growth [1,2,3](Fig 1A)
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Cells respond to their environment by making proteins using transcription and translation of mRNA
Modest observed correlations between global steady-state mRNA and protein measurements have been interpreted as evidence that mRNA levels determine roughly 40% of the variation in protein levels, indicating dominant post-transcriptional effects
Summary
Cellular protein levels reflect the balance of mRNA levels, protein production by translation initiation and completion, and protein removal by degradation, secretion, and dilution due to growth [1,2,3](Fig 1A). The mRNA–protein correlation observed in global measurements of mRNA and protein levels has been intensely studied, and deviations from perfect correlation used to quantify the contribution of post-transcriptional processes to cellular protein levels [1, 3, 6,7,8,9] The consensus across these studies holds that, in a wide array of organisms, transcriptional regulation explains 30–50% of the variation in steady-state protein levels, leaving half or more to be explained by post-transcriptional regulatory processes [3, 7, 9,10,11,12,13,14,15,16]. Recent studies have uncovered wide between-gene variation in post-transcriptional features such as inferred translation rates [18] and protein degradation rates [3]
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