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. 2009;5:312.
doi: 10.1038/msb.2009.70. Epub 2009 Oct 13.

Global Effects of DNA Replication and DNA Replication Origin Activity on Eukaryotic Gene Expression

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Free PMC article

Global Effects of DNA Replication and DNA Replication Origin Activity on Eukaryotic Gene Expression

Larsson Omberg et al. Mol Syst Biol. .
Free PMC article

Abstract

This report provides a global view of how gene expression is affected by DNA replication. We analyzed synchronized cultures of Saccharomyces cerevisiae under conditions that prevent DNA replication initiation without delaying cell cycle progression. We use a higher-order singular value decomposition to integrate the global mRNA expression measured in the multiple time courses, detect and remove experimental artifacts and identify significant combinations of patterns of expression variation across the genes, time points and conditions. We find that, first, approximately 88% of the global mRNA expression is independent of DNA replication. Second, the requirement of DNA replication for efficient histone gene expression is independent of conditions that elicit DNA damage checkpoint responses. Third, origin licensing decreases the expression of genes with origins near their 3' ends, revealing that downstream origins can regulate the expression of upstream genes. This confirms previous predictions from mathematical modeling of a global causal coordination between DNA replication origin activity and mRNA expression, and shows that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Significant and unique HOSVD combinations, that is, subtensors (Table I and Supplementary Figures 8–11). (A) Bar charts for the fractions of mRNA expression that the seven most significant combinations capture in the data cuboid. The fourth combination S(4,1,2), of the fourth pattern across the genes, the first across the time points and the second across the biological conditions, captures ∼2.7% of the expression of the 4270 genes. (B) Line-joined graphs of the first (red), second (blue) and third (green) expression patterns across the time points. The color bars indicate the cell cycle classifications of the time points in the averaged Cdc6+/45+ control (Supplementary Figure 7) as described (Spellman et al, 1998): M/G1 (yellow), G1 (green), S (blue), S/G2 (red) and G2/M (orange). The grid line separates the even and odd hybridization batches, indicated by black arrows. The first pattern is approximately time invariant. The second and third patterns describe oscillations consistent within the hybridization batches, that peak at the M/G1 and G1/S phases and trough at the S/G2 and G2/M phases, respectively. (C) Line-joined graphs of the first (red), second (blue) and third (green) patterns across the conditions. The first pattern is condition invariant. The second pattern correlates with underexpression in both conditions in which DNA replication is prevented, that is, in both Cdc6 and Cdc45 cells, relative to the averaged Cdc6+/45+ control. The third pattern correlates with overexpression in the Cdc6 cells and underexpression in the Cdc45 cells relative to the averaged control.
Figure 2
Figure 2
The averaged data cuboid of mRNA expression of the 4270 genes across the 12 time points and across the three biological conditions (Supplementary information Dataset 3). Raster display with overexpression (red), no change in expression (black) and underexpression (green), where the expression of each gene is centered at its time-invariant level. The genes are sorted by their angular distances θ:=arctan(U:3/U:2) between the second and third HOSVD combinations (Supplementary information Section 2.6), which represent the unperturbed cell cycle expression oscillations (Box 1 and Supplementary Figure 12). The white lines separate the even and odd hybridization batches, indicated by black arrows. The picture of global expression oscillations in the averaged Cdc6+/45+ control time course is consistent with previous genome-wide mRNA expression analyses of synchronized Saccharomyces cerevisiae cultures (Alter et al, 2000; Alter and Golub, 2004; Alter, 2006; Li and Klevecz, 2006; Klevecz et al, 2008). The picture that emerges is that of unperturbed global expression oscillations that are dominant in the Cdc6, Cdc45 as well as in the Cdc6+/45+ time courses.
Figure 3
Figure 3
DNA replication-dependent and Mcm2–7 origin binding-dependent gene expression. Raster display, in which the expression of each gene is centered at its time-invariant level. (A) DNA replication is required for efficient histone gene expression. Raster display of histone gene expression shows that histone genes are overexpressed in the Cdc6+/45+ control, relative to the Cdc6 condition, and to a lesser extent also relative to the Cdc45 condition, in a highly correlated manner. (B) Origin licensing decreases the expression of genes with origins near their 3′ ends. Raster display of the expression of the 16 most significant genes in this class shows that these genes are overexpressed in the Cdc6 relative to the Cdc45 time courses, and to a lesser extent also relative to the control, in a manner less correlated than that of the histone genes.

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