Network-dosage compensation topologies as recurrent network motifs in natural gene networks.

Ruijie Song,Murat Acar,Ping Liu

doi:10.1186/1752-0509-8-69

Abstract

BackgroundGlobal noise in gene expression and chromosome duplication during cell-cycle progression cause inevitable fluctuations in the effective number of copies of gene networks in cells. These indirect and direct alterations of network copy numbers have the potential to change the output or activity of a gene network. For networks whose specific activity levels are crucial for optimally maintaining cellular functions, cells need to implement mechanisms to robustly compensate the effects of network dosage fluctuations.ResultsHere, we determine the necessary conditions for generalized N-component gene networks to be network-dosage compensated and show that the compensation mechanism can robustly operate over large ranges of gene expression levels. Furthermore, we show that the conditions that are necessary for network-dosage compensation are also sufficient. Finally, using genome-wide protein-DNA and protein-protein interaction data, we search the yeast genome for the abundance of specific dosage-compensation motifs and show that a substantial percentage of the natural networks identified contain at least one dosage-compensation motif.ConclusionsOur results strengthen the hypothesis that the special network topologies that are necessary for network-dosage compensation may be recurrent network motifs in eukaryotic genomes and therefore may be an important design principle in gene network assembly in cells.

Highlights

Global noise in gene expression and chromosome duplication during cell-cycle progression cause inevitable fluctuations in the effective number of copies of gene networks in cells
Mathematical analysis of network-dosage compensation in N-component gene networks To investigate the necessary and sufficient conditions that can make an N-component gene network dosagecompensated, we consider a network composed of N genes that are under the control of the same transcription factor (TF)
Recurrent nature of the dosage-compensation motifs in the Saccharomyces cerevisiae genome To find out how frequently the dosage compensation structures occur in the yeast genome, we examined a set of 1,385 genes that have regulatory roles in S. cerevisiae, and 166 transcription factors (TF) that, in turn, regulate their transcription (Figure 5 and Additional files 2, 3)

Summary

Introduction

Global noise in gene expression and chromosome duplication during cell-cycle progression cause inevitable fluctuations in the effective number of copies of gene networks in cells. The effective dosage of a gene network – the number of network copies in a cell – can vary significantly both throughout a cell’s lifetime and across different cells in the same clonal population Such changes can arise from a variety of direct and indirect causes. DNA replication during the cell cycle [1] would double the network dosage, and it has been shown that many promoters display an increase in transcription consistent with gene dosage effects during the G2 phase of the cell cycle as compared to G1 [2] Organisms such as yeast that switch between haploid and diploid life. Outside of a trivial case, 1-component networks could not be dosage invariant, but 2-component networks could be if they satisfied certain criteria: the two components had to have different regulatory signs, they had to interact with a 1:1 stoichiometry, and the effects of one of the two components had to be indirect and exerted its effects on transcription through action on the other component [10]

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Discussion

Conclusion