Journal Article

Global effects of DNA replication and DNA replication origin activity on eukaryotic gene expression

Alter, Orly, Diffley, John F X, Drury, Lucy S, Meyerson, Joel R, Omberg, Larsson, Kobayashi, Kayta

2009

Overview

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, ∼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. In this first global view of how DNA replication affects transcription, ∼88% of global gene expression is found to be independent of DNA replication, significantly lowering the recently measured upper bound to replication‐dependent mRNA expression. The requirement of DNA replication for efficient histone gene expression is found to be independent of conditions that elicit DNA damage checkpoint responses. Origin licensing is found to decrease expression of genes with origins near their 3′ ends, experimentally revealing for the first time that downstream origins can regulate the expression of upstream genes, and demonstrating that mathematical modeling of DNA microarray data can be used to correctly predict previously unknown biological modes of regulation. The recent analogy of the tensor higher‐order singular value decomposition (HOSVD) with the matrix singular value decomposition (SVD), which already enables the interpretation of the HOSVD in terms of the cellular states, biological processess and experimental artifacts that compose the data tensor, is extended by mathematically defining the operation of HOSVD data reconstruction, and by computationally using this operation to remove experimental artifacts from the data.

• Publisher: Nature Publishing Group UK,John Wiley & Sons, Ltd,EMBO Press,Nature Publishing Group,Springer Nature
• Subject: a higher‐order singular value decomposition (HOSVD) / Artifact identification / Cell cycle / Datasets / Deoxyribonucleic acid / DNA / DNA biosynthesis / DNA chips / DNA damage / DNA microarrays / DNA Replication - genetics / DNA replication origin licensing and firing / EMBO06 / EMBO09 / Gene expression / Gene Expression Regulation, Fungal / Genes / Genes, Fungal / Genomes / Licenses / Mathematical analysis / Mathematical models / Medical research / mRNA expression / Origins / Replication / Replication initiation / Replication Origin - genetics / Replication origins / RNA, Messenger - genetics / RNA, Messenger - metabolism / Saccharomyces cerevisiae / Saccharomyces cerevisiae - genetics / Saccharomyces cerevisiae Proteins - genetics / Saccharomyces cerevisiae Proteins - metabolism / Singular value decomposition / Time Factors / Transcription factors / Yeast