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

Abstract

doi: bioRxiv preprint first posted online Nov. 26, 2015; 2 Standfirst textUsing a new statistical tool to analyze time-series protein and matching mRNA concentration data, this study deconvoluted the contributions of mRNA and protein level regulation in the response of mammalian cells to stress of the endoplasmatic reticulum.-We quantified protein and mRNA concentrations for 3,235 genes across two replicates and time points, with a high-confidence dataset of 1,237 genes/mRNAs.-We use a new statistical tool to quantify the contribution of regulatory processes, and we find that mRNA and protein level regulation play similarly important roles.-mRNA and protein level regulation have different dynamics: mRNA concentrations spike in their change and return to pre-perturbation levels, while protein concentrations switch in their behavior and reach a new steady-state.-We generated hypotheses on modes of regulation for several groups of genes.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.Thecopyright holder for this preprint . http://dx.doi.org/10.1101/032797 doi: bioRxiv preprint first posted online Nov. 26, 2015; 3 AbstractThe 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 the proteomics and transcriptomics changes in mammalian cells responding to stress induced by dithiothreitol over 30 hours. Specifically, we estimated the kinetic parameters for synthesis and degradation of RNA and proteins, and deconvoluted response patterns common and unique to each regulatory level using a new statistical tool. Overall, both 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. Further, mRNA concentrations were regulated in a transient, spike-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 example groups of genes. Words: 173 (of 175 max)All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx

The interdependence of transcript and protein abundance: new data–new complexities

“…In their recent work, Cheng et al () extended this line of research to a third experimental system. They studied the dynamics of transcript and protein profiles in HeLa cells following induction of ER stress by dithiothreitol (DTT) treatment.…”

“…ER stress is known to activate the unfolded protein response (UPR) that can restore normal cellular function in stressed cells by halting protein translation, removing the misfolded proteins and re‐arranging the cellular proteome. Therefore, the system of severe ER stress investigated by Cheng et al () induces a vital, substantial, and pleiotropic cellular response, a situation that is in stark contrast to cells in steady state or after the stimulation of specific signaling systems (Fig ). In comparison, the LPS stimulation of dendritic cells seems to trigger a substantially milder burden to the cells with a much lower fraction of cell death being apparent (personal communication with Marko Jovanovic) (Jovanovic et al , ).…”

“… The relative contribution of transcriptional and translational regulation in gene expression control remains an open question. Vogel and colleagues (Cheng et al , ) show that the endoplasmic reticulum stress response is controlled at both the transcript and protein levels.

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Integration of large-scale multi-omic datasets: A protein-centric view

“…In response to a reagent causing accumulation of unfolded proteins in the endoplasmic reticulum, relative contributions of transcription and translation were much more balanced, and protein changes often differed from those of RNA in a non-linear manner [48]. In addition, transcript abundances changed more acutely than protein abundances and in most cases RNA returned to initial states by the end of the 30 hour experiment.…”

Changes in transcript and protein expression levels in the barley — Cochliobolus sativus interaction

“…However, proteomic studies provide information on post-translational modifications, which cannot be obtained from mRNA expression profiles; these have proven critical to our understanding of proper physiological protein function, translocation, and subcellular localization (Bastiaanse et al 2014;Liu and Aebersold 2016). Understanding the mutual regulatory interactions between transcriptome and proteome necessitates an approach that encompasses the simultaneous monitoring of expression at both the RNA and protein levels (Cheng et al 2016).…”