Uncovering the kinetic fingerprints of transcriptional control using gene expression dynamics

Synopsis

Gene regulation is central to cellular function. Yet, while decades of biochemical and genetic studies have established a reasonably complete “parts list” of the molecular components required for eukaryotic transcription, we nonetheless lack quantitative models that can predict how these pieces interact in space and time to give rise to robust gene regulatory logic. For this talk, I will cover three interrelated vignettes from my Ph.D. that combine in vivo microscopy, statistical methods, and theoretical modeling to dissect the molecular underpinnings of transcriptional control in the developing fruit fly embryo. To begin, I discuss results from a project that utilizes a novel statistical technique and live single-cell measurements of transcription to uncover how transcription factors modulate the kinetics of the transcriptional cycle to produce a sharp stripe of gene expression. Next, I share recent experimental results that utilize cutting-edge optogenetic methods to rapidly export repressor proteins from cells, revealing that transcriptional repression—and the development trajectories it dictates—is rapidly reversible. To close, I examine the question of gene regulation through the lens of statistical physics, using simple kinetic models to dissect how transcription factor binding transmits information to drive cellular decisions. These calculations reveal that the dissipation of biochemical energy can accelerate the rate of information transfer by orders of magnitude, and suggest that nonequilibrium gene regulatory mechanisms may be necessary in order for gene loci to function in the context of crowded cellular environments.