10:30 am
GCIS Room E123
"Uncovering the kinetic fingerprints of transcriptional control using gene expression dynamics"
Predicting how the gene expression patterns that specify animal body plans arise from interactions
between transcription factor proteins and regulatory DNA remains a major challenge in physical biology. We utilize live imaging, computational modeling, and theoretical approaches to examine how transcriptional control at the single cell level gives rise to a sharp stripe of cytoplasmic mRNA in the fruit fly embryo. We find that the frequency of transcriptional bursts is modulated across the stripe to control the mRNA production rate. In addition to this mean rate modulation, we find that repressors function to control the window of time over which nuclei transcribe by inducing the early cessation of transcription in cells on the stripe flanks.
This all-or-none control of the transcriptional time window is critical to stripe formation, and, in the
normal course of development, appears irreversible. However, by using novel optogenetic tools to
export repressor proteins from silenced nuclei, we reveal that this switch-like silencing is, in fact, rapidly reversible (on timescales of 1-2 minutes), and that it originates from the sharp down-regulation of burst frequency by transcriptional repressors. Thus, we uncover a surprising unity, with both mean rate modulation and control of the transcriptional time window emerging from the same step of the transcriptional cycle.
To close, I outline ongoing theoretical work that moves beyond phenomenological models of
transcriptional bursting to consider a molecular picture of how transcription factor binding transmits information to drive cellular decisions. We demonstrate that the separation of timescales between rapid binding and slow transcriptional bursting can lead to non-intuitive behaviors wherein multiple binding events at a single binding site can regulate multiple stages of the transcriptional cycle. We find that this kinetic cooperativity dramatically increases the rate of information transfer, but only in gene loci that dissipate biochemical energy to operate away from thermodynamic equilibrium.
In this talk, I will discuss our recent contributions in three areas: molecular robots, information-processing circuits, and reconfigurable DNA nanostructures.