Differential dynamics of the mammalian mRNA and protein expression response to misfolding stress

Abstract

The relative importance of regulation at the mRNA versus protein level is subject to ongoing debate. To address this question in a dynamic system, we mapped proteomic and transcriptomic changes in mammalian cells responding to stress induced by dithiothreitol over 30 h. Specifically, we estimated the kinetic parameters for the synthesis and degradation of RNA and proteins, and deconvoluted the response patterns into common and unique to each regulatory level using a new statistical tool. Overall, the two regulatory levels were equally important, but differed in their impact on molecule concentrations. Both mRNA and protein changes peaked between two and eight hours, but mRNA expression fold changes were much smaller than those of the proteins. mRNA concentrations shifted in a transient, pulse‐like pattern and returned to values close to pre‐treatment levels by the end of the experiment. In contrast, protein concentrations switched only once and established a new steady state, consistent with the dominant role of protein regulation during misfolding stress. Finally, we generated hypotheses on specific regulatory modes for some genes.

Proteomic analysis of xylem vessel cell differentiation in VND7-inducible tobacco BY-2 cells by two-dimensional gel electrophoresis

“…The expression of functional proteins is tightly regulated at the post-transcriptional level, including translational regulation and post-translational modification (Cheng et al 2016;Liu and Aebersold 2016;Peng et al 2015;Vogel and Marcotte 2012). Likewise, our comparative 2DE analysis showed that post-transcriptional regulation has a large impact on the expression of functional proteins during xylem vessel cell differentiation.…”

“…Recent comparative studies between proteomic and transcriptomic data revealed low correlations for a certain number of genes (Cheng et al 2016;Liu and Aebersold 2016;Peng et al 2015;Vogel and Marcotte 2012). The expression of functional proteins is tightly regulated at the post-transcriptional level, including translational regulation and post-translational modification (Cheng et al 2016;Liu and Aebersold 2016;Peng et al 2015;Vogel and Marcotte 2012).…”

Predictive biophysical modeling and understanding of the dynamics of mRNA translation and its evolution

“…Surprisingly, generally there is only a limited degree of correlation between the levels of mRNAs and their encoded proteins (1–4), emphasizing the significant effect of post-transcriptional regulation on protein levels.…”

“…In recent years, various large scale techniques for estimating variables related to mRNA translation have been developed (1,3–4,24–41). Thus, in the recent and following years computational models of translation on the basis of high-throughput, genome-wide datasets, are expected to be instrumental in deciphering this process (1–2,7,12,19,42–70).…”

Evolving insights into RNA modifications and their functional diversity in the brain

“…When translation rate constants are included the correlation is much stronger, which suggests that the rate of translation, and not necessarily the overall levels of mRNA in a cell, may be a dominant process that controls protein expression 6 . However, this view has recently been challenged by the observation that the kinetics of both synthesis and degradation of RNA and protein are equally involved in regulating cellular homeostasis in response to an acute stressor 7 . Jovanovic et al 8 note that RNA abundance contributes significantly to protein levels at steady state in immune cells and that this relationship is even more pronounced following stimulation, in accordance with the idea that translation and degradation might predominate, although in a context-specific manner 9 .…”