Impulse control: temporal dynamics in gene transcription

Abstract

Regulatory circuits controlling gene expression constantly rewire to adapt to environmental stimuli, differentiation cues, and disease. We review our current understanding of the temporal dynamics of gene expression in eukaryotes and prokaryotes and the molecular mechanisms that shape them. We delineate several prototypical temporal patterns, including "impulse" (or single-pulse) patterns in response to transient environmental stimuli, sustained (or state-transitioning) patterns in response to developmental cues, and oscillating patterns. We focus on impulse responses and their higher-order temporal organization in regulons and cascades and describe how core protein circuits and cis-regulatory sequences in promoters integrate with chromatin architecture to generate these responses.

Figure 1. Prototypical patterns of temporal dynamics of gene expression

Schematic views of gene expression levels (y-axis; arbitrary units) over time (x-axis) commonly found in cells in steady state or during response to environmental, developmental, or pathenogenic stimuli. Blue and red plots show possible profiles for different genes under each category. Example functions are noted in bullet points.

Figure 2. General network motifs in transcriptional regulatory networks

Shown are general motifs found in transcriptional regulatory networks. Nodes represent proteins; edges are directed from a DNA-binding protein to a protein encoded by a genes to which it binds to and regulates. Arrows and blunt-arrows represent activation and repression, respectively; circle-ending arrows are either activation (+) or repression (-). Relevant functions are noted in bullet points.

Figure 3. Promoter regions and nucleosome positioning as temporal signal processors

(a) The transcription factor Pho4 (orange oval) targets different variants of the Pho5 promoter following phosphate starvation in yeast cells (left). The purple (upper) promoter contains the wild-type Pho5 binding sequence, whereas the green and red promoters (denoted as H1 and H3 respectively) are synthetic variants. Each target exhibits a different response time (right) depending on the affinity of Pho4 for its binding site when the site is unoccluded by nucleosomes (depicted in panel b). The y-axis corresponds to median fluorescence levels, across separate measurements, scaled between the promoter-specific expression minimum at 0 h and maximum at 7 hours after induction. (b) Suggested mechanism for decoupling promoter induction threshold from dynamic range. Cartoons of Pho4 and nucleosome occupancies at the three Pho4 promoter variants under mild (top) and acute (bottom) phosphate starvation. Gray and yellow ovals represent nucleosomes and Pho4, respectively; blue circles and red triangles correspond to low-affinity and high-affinity binding sites, respectively; and, X marks ablation of the Pho4 binding motif. The opacity of grey ovals indicates nucleosome occupancy. Under intermediate levels of phosphate (top), substantial Pho4 occupancy and subsequent transcriptional activity occurs at promoters only with exposed high-affinity sites. The plot to the right shows the respective expression levels, divided for each variant by the maximum level at full starvation. In the absence of phosphate (bottom), Pho4 activity is saturated, resulting in nucleosome eviction and maximum expression at all promoters. The plot to the right shows the respective maximal induction levels in arbitrary units (a.u.). Reproduced from (Lam et al., 2008), with permission from the authors.

Figure 4. Coordinated impulse response generated by protein oscillators

(a) In response to extracellular calcium, yeast cells initiate bursts of nuclear localization of the transcription factor Crz1. Bottom left: A single-cell time trace of the amount of phosphoryalted Crz1 in the nucleus over time; the arrow indicates introduction of extracellular calcium. Bottom right: The frequency of bursts (y-axis) rises with calcium levels (x-axis). Error bars calculated by using different thresholds for burst determination (see (Cai et al., 2008)). Inset: A histogram of burst duration times under high (red) and low (blue) calcium levels indicates that burst duration is independent of calcium concentration. (b) Expression levels of three synthetic Crz1-dependent promoters increase proportionally to extracellular calcium concentration (x-axis). On the y-axis, data is divided, for each variant, by the expression at maximum calcium level. The synthetic promoters have 1 (red), 2 (green), or 4 (blue) calcineurin-dependent response elements. Inset: fold change of the different targets, following Crz1 over expression. The targets exhibit different responses, probably due to their different numbers of Crz1 binding sites. Reproduced from (Cai et al., 2008), with permission from the authors.