Invited Talk: Signal-Dependent Transcriptional Regulation for Cell Fate Control

Activation and inactivation of kinases in a signaling pathway induce various expression patterns in downstream inducible genes. Although many extracellular stimuli show remarkably similar profiles in terms of immediate early gene (IEG) mRNA expression, the biological outcomes in response to these stimuli can vary. Using mammalian cell models, we quantitatively study signal-dependent IEG regulation to identify common regulatory mechanisms in the process of cell fate decision. We found that dynamics of the signaling pathways is critical to determine amplitude and dose responses of IEG expression, and that their dynamics is controlled by post-transcriptional (rapid) or transcriptional (delayed) feedback regulations. Sustained signaling activities contribute for a binary activation of some of the transcription factors belong to IEG, thus a coordinated regulation of signals and IEGs quickly make the first decision in a time-course cell fate trajectory. We recently study transcription factor binding and chromatin openings (epigenetic changes) in this process. Our study combined with bioinformatics analysis and mathematical modeling indicates that cooperative intermolecular interactions in enhancer regulation transduce a property of signaling dynamics to a set of associated genes in a switch-like manner as revealed by single cell transcriptome.