Robustness of transcriptional regulatory program influences gene expression variability

Zhiming Dai,Jihua Feng,Xianhua Dai,Qian Xiang

doi:10.1186/1471-2164-10-573

Abstract

BackgroundMost genes are not affected when any transcription factor (TF) is knocked out, indicating that they have robust transcriptional regulatory program. Yet the mechanism underlying robust transcriptional regulatory program is less clear.ResultsHere, we studied the cause and effect of robust transcriptional regulatory program. We found that cooperative TFs in the robust transcriptional regulatory program regulate their common target genes in an activity-redundant fashion, and they are able to compensate for each other's loss. As a result, their target genes are insensitive to their single perturbation. We next revealed that the degree of robustness of transcriptional regulatory program influences gene expression variability. Genes with fragile (unrobust) transcriptional regulatory program under normal growth condition could be readily reprogrammed to significantly modulate gene expression upon changing conditions. They also have high evolutionary rates of gene expression. We further showed that the fragile transcriptional regulatory program is a major source of expression variability.ConclusionWe showed that activity-redundant TFs guarantee the robustness of transcriptional regulatory programs, and the fragility of transcriptional regulatory program plays a major role in gene expression variability. These findings reveal the mechanisms underlying robust transcription and expression variability.

Highlights

Most genes are not affected when any transcription factor (TF) is knocked out, indicating that they have robust transcriptional regulatory program
If a given TF is involved in the fragile transcriptional regulatory program, the expression of its cohort genes should be significantly affected by its knockout
We used the Kolmogorov-Smirnov (K-S) statistical test to measure the discrepancy in the distribution of TFknockout gene expression values between a given TF cohort and the rest of the genes

Summary

Introduction

Most genes are not affected when any transcription factor (TF) is knocked out, indicating that they have robust transcriptional regulatory program. The mechanism underlying robust transcriptional regulatory program is less clear. Gene expression can be regulated at multiple levels, one of the most important regulatory mechanisms is at the transcriptional level. The transcriptional program is regulated by binding of transcription factors (TFs) to the specific DNA sequences in regulatory regions of the genes. TFs are fundamental to the regulation of gene expression. Several studies on specific TFs have observed that only a small fraction of genes that were bound by a TF were differentially expressed after that factor was knocked out or knocked down [1,2,3,4]. Further analysis showed that there is only a low overlap (~3%) between the knockout targets and the binding targets identified by chromatin immunoprecipitation (ChIP)-chip [6]

Methods

Results

Discussion

Conclusion