Eukaryotic gene regulation as frequency modulation

23 October 2015

Thomas Höfer
Division of Theoretical Systems Biology
DKFZ, Heidelberg, Germany


Studies of bacterial gene regulation have emphasized the role of transcriptional activators as structural scaffolds for the assembly of the pre-initiation complex. This concept is often considered universal and has been quantified using equilibrium statistical physics. For eukaryotes, however, the short dwell times of transcription factors at their cognate sites and the enzymatic nature of transcriptional activation argue against equilibrium models. Based on these ideas, I will discuss a family of mathematical models for transcription factors acting as modulators of burst-like mRNA synthesis from eukaryotic promoters. Confronting these models with time-resolved chromatin-immunoprecipitation, mRNA and protein data of a natural optogenetic system, we find that the light-controlled transcription factor regulates the frequency of transcriptional bursts of its target genes. The corresponding model predicts, and experiments verify, that frequency modulation of a refractory bursting cycle overcomes physical constraints on response sensitivity and speed inherent in the equilibrium model.

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