Dynamic cumulative activity of transcription factors as a mechanism of quantitative gene regulation.
BACKGROUND
The regulation of genes in multicellular organisms is generally achieved through the combinatorial activity of different transcription factors. However, the quantitative mechanisms of how a combination of transcription factors controls the expression of their target genes remain unknown.


RESULTS
By using the information on the yeast transcription network and high-resolution time-series data, the combinatorial expression profiles of regulators that best correlate with the expression of their target genes are identified. We demonstrate that a number of factors, particularly time-shifts among the different regulators as well as conversion efficiencies of transcription factor mRNAs into functional binding regulators, play a key role in the quantification of target gene expression. By quantifying and integrating these factors, we have found a highly significant correlation between the combinatorial time-series expression profile of regulators and their target gene expression in 67.1% of the 161 known yeast three-regulator motifs and in 32.9% of 544 two-regulator motifs. For network motifs involved in the cell cycle, these percentages are much higher. Furthermore, the results have been verified with a high consistency in a second independent set of time-series data. Additional support comes from the finding that a high percentage of motifs again show a significant correlation in time-series data from stress-response studies.


CONCLUSIONS
Our data strongly support the concept that dynamic cumulative regulation is a major principle of quantitative transcriptional control. The proposed concept might also apply to other organisms and could be relevant for a wide range of biotechnological applications in which quantitative gene regulation plays a role.
He
Feng
F
Biological Systems Analysis Group, HZI- Helmholtz Centre for Infection Research, Inhoffenstrasse, D-38124 Braunschweig, Germany.
Buer
Jan
J
Zeng
An-Ping
AP
Balling
Rudi
R
D000465:Algorithms; D020816:Amino Acid Motifs; D001665:Binding Sites; D001709:Biotechnology / Q000379:methods; D002453:Cell Cycle; D005189:False Positive Reactions; D005656:Fungal Proteins / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D008957:Models, Genetic; D008962:Models, Theoretical; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic