- BS, UW-Madison, 2008.
Advances in single-cell microscopy have revealed that cells transmit environmental information into distinct gene expression responses by modulating transcription factor (TF) activity over time. In a scheme somewhat analogous to Morse code, the identity and dose of a given stimulus can be encoded in the frequency, duration, and amplitude of oscillations in TF activity. Just as Morse code enables a simple on-off switch to communicate virtually any message, TF dynamics allow a single TF to elicit distinct gene expression programs in response to different stimuli. Such behavior is conserved across kingdoms—in the bacteria Bacillus subtilis, sigma factor ?? activity oscillates with increasing frequency in response to higher levels of energy stress, while the mammalian tumor suppressor p53 exhibits pulses of activity in response to ?-radiation, but sustained activity in response to UV radiation. The yeast Saccharomyces cerevisiae multi-stress regulator Msn2 also exhibits stimulus-specific TF dynamics. Msn2 is a zinc-finger TF that is active when localized to the nucleus where it can bind DNA and induce gene expression. Oxidative stress causes sustained activation of Msn2 with dose-dependent amplitude; glucose starvation causes bursts of activation with dose-dependent frequency; and osmotic stress causes an initial pulse of activation with dose-dependent duration.
Such stimulus-specific TF dynamics are becoming well-known as more single-cell imaging studies are performed. However, the mechanisms by which TF dynamics are decoded by promoters and other regulatory elements to generate distinct gene expression responses are poorly understood. I am interested in developing a generalized technique for controlling TF activity to characterize these mechanisms and in constructing synthetic gene circuits that exploit them.