Embedding mRNA Stability in Correlation Analysis of Time-Series Gene Expression Data

Abstract

Current methods for the identification of putatively co-regulated genes directly from gene expression time profiles are based on the similarity of the time profile. Such association metrics, despite their central role in gene network inference and machine learning, have largely ignored the impact of dynamics or variation in mRNA stability. Here we introduce a simple, but powerful, new similarity metric called lead-lag R² that successfully accounts for the properties of gene dynamics, including varying mRNA degradation and delays. Using yeast cell-cycle time-series gene expression data, we demonstrate that the predictive power of lead-lag R² for the identification of co-regulated genes is significantly higher than that of standard similarity measures, thus allowing the selection of a large number of entirely new putatively co-regulated genes. Furthermore, the lead-lag metric can also be used to uncover the relationship between gene expression time-series and the dynamics of formation of multiple protein complexes. Remarkably, we found a high lead-lag R² value among genes coding for a transient complex. Microarrays provide snapshots of the transcriptional state of the cell at some point in time. Multiple snapshots can be taken sequentially in time, thus providing insight into the dynamics of change. Since genome-wide expression data report on the abundance of mRNA, not on the underlying activity of genes, we developed a novel method to relate the expression pattern of genes, detected in a time-series experiment, using a similarity measure that incorporates mRNA decay and called lead-lag R². We used the lead-lag R² similarity measure to predict the presence of common transcription factors between gene pairs using an integrated dataset consisting of 13 yeast cell-cycles. The method was benchmarked against six well-established similarity measures and obtained the best true positive rate result, around 95%. We believe that the lead-lag analysis can be successfully used also to predict the presence of a common mechanism able to modulate the degradation rate of specific transcripts. Finally, we envisage the possibility to extend our analysis to different experimental conditions and organisms, thus providing a simple off-the-shelf computational tool to support the understanding of the transcriptional and post-transcriptional regulation layer and its role in many diseases, such as cancer.