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

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.\n\n- 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.\n- 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.\n- 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.\n- We generated hypotheses on modes of regulation for several groups of genes.\n\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=87 SRC=\"FIGDIR/small/032797_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (21K):\norg.highwire.dtl.DTLVardef@97d00corg.highwire.dtl.DTLVardef@dbe5fborg.highwire.dtl.DTLVardef@d801c7org.highwire.dtl.DTLVardef@15cd52d_HPS_FORMAT_FIGEXP M_FIG C_FIG 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.