Systematic identification of signal-activated stochastic gene regulation.
Although much has been done to elucidate the biochemistry of signal transduction and gene regulatory pathways, it remains difficult to understand or predict quantitative responses. We integrate single-cell experiments with stochastic analyses, to identify predictive models of transcriptional dynamics for the osmotic stress response pathway in Saccharomyces cerevisiae. We generate models with varying complexity and use parameter estimation and cross-validation analyses to select the most predictive model. This model yields insight into several dynamical features, including multistep regulation and switchlike activation for several osmosensitive genes. Furthermore, the model correctly predicts the transcriptional dynamics of cells in response to different environmental and genetic perturbations. Because our approach is general, it should facilitate a predictive understanding for signal-activated transcription of other genes in other pathways or organisms.
Departments of Physics and Biology and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Gregor
G
Neuert
Brian
B
Munsky
Rui Zhen
RZ
Tan
Leonid
L
Teytelman
Mustafa
M
Khammash
Alexander
A
van Oudenaarden
D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D006360:Heat-Shock Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008957:Models, Genetic; D015233:Models, Statistical; D009995:Osmosis; D009997:Osmotic Pressure; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D015398:Signal Transduction; D059010:Single-Cell Analysis / Q000379:methods*; D013269:Stochastic Processes; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C112591:HSP12 protein, S cerevisiae; D006360:Heat-Shock Proteins; D026901:Membrane Transport Proteins; C470555:STL1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins