An integrated systems approach for understanding cellular responses to gamma radiation

Abstract

Cellular response to stress entails complex mRNA and protein abundance changes, which translate into physiological adjustments to maintain homeostasis as well as to repair and minimize damage to cellular components. We have characterized the response of the halophilic archaeon Halobacterium salinarum NRC-1 to (60)Co ionizing gamma radiation in an effort to understand the correlation between genetic information processing and physiological change. The physiological response model we have constructed is based on integrated analysis of temporal changes in global mRNA and protein abundance along with protein-DNA interactions and evolutionarily conserved functional associations. This systems view reveals cooperation among several cellular processes including DNA repair, increased protein turnover, apparent shifts in metabolism to favor nucleotide biosynthesis and an overall effort to repair oxidative damage. Further, we demonstrate the importance of time dimension while correlating mRNA and protein levels and suggest that steady-state comparisons may be misleading while assessing dynamics of genetic information processing across transcription and translation.

Figure 1

Systems level visualization during early response to γ radiation for all genes showing systematic and significant expression changes with the layout organized by general function. The RNA changes are visualized as a network of genes (nodes) and their interactions (edges). The color of the nodes indicates upregulation (red) or downregulation (green) of that gene, whereas the size of the node relates to the significance of the observed change (λ value; see legend). Edge types are color coded to delineate the association type (see legend).

Figure 2

Graphical representation of the systems level response in Halobacterium NRC-1 to direct and indirect effects of γ radiation showing both repair and oxidative strategies for cell recovery. Text or arrow color indicates whether the cellular process or pathway was upregulated (red) or downregulated (green). Green X's indicate downregulated steps in the TCA cycle. Blue ellipses represent Htr8 and Htr12.

Figure 3

Time-lagged Pearson correlations between mRNA and protein abundance for genes with significant changes in both. The time lag is given on the side ranging from 30 min (Δ30m) to no shift (Δ0m). P-values indicate the statistical significance of the distribution of Pearson coefficients and are only stated when a significant skew is observed. P-values on the right of the dashed line indicate a skew towards positive correlations, whereas those on the left indicate a negative correlation.