Noise Can Induce Bimodality in Positive Transcriptional Feedback Loops Without Bistability

Abstract

Transcriptional positive-feedback loops are widely associated with bistability, characterized by two stable expression states that allow cells to respond to analog signals in a digital manner. Using a synthetic system in budding yeast, we show that positive feedback involving a promoter with multiple transcription factor (TF) binding sites can induce a steady-state bimodal response without cooperative binding of the TF. Deterministic models of this system do not predict bistability. Rather, the bimodal response requires a short-lived TF and stochastic fluctuations in the TF's expression. Multiple binding sites provide these fluctuations. Because many promoters possess multiple binding sites and many TFs are unstable, positive-feedback loops in gene regulatory networks may exhibit bimodal responses, but not necessarily because of deterministic bistability, as is commonly thought.

Two DNA-encoded strategies for increasing expression with opposing effects on promoter dynamics and transcriptional noise

“…Mutating a TATA-box in two yeast promoters reduces expression variability, in a manner that is consistent with an effect of TATA-boxes on the size of transcriptional bursts (Raser and O'Shea 2004;Blake et al 2006;Hornung et al 2012). The number and affinity of transcription factor binding sites were also shown to affect expression variability (Murphy et al 2007;To and Maheshri 2010;Suter et al 2011), with one study demonstrating that using two sites for the mammalian transcription factor NF-Y instead of one, or using a higher affinity NF-Y site, increased expression variability in an artificial promoter construct (Suter et al 2011). Similar to the effect of TATA-boxes, the increase in expression variability observed with two NF-Y sites or with a higheraffinity site was mediated primarily by an increase in the average burst size, whereas the burst frequency was largely unaffected (Suter et al 2011).…”

Transcription factor levels enable metabolic diversification of single cells of environmental bacteria

“…As IHF is not a limiting factor, reducing IHF only increases deactivation frequency (mid panel in Figure 5b, right), that is, Pu undergoes frequent deactivation events but of short duration, as the high amount of Ra present (upper panel in Figure 5b, right), compensates eventual dissociations of IHF from the Pu promoter. The basic effect of these fast inactivation events is to increase the size of transcriptional bursts (lower panel in Figure 5b, right), and hence the noise, but is not enough to create bimodality, which requires the presence of slow promoter fluctuations (To and Maheshri, 2010). The outcome of these numerical experiments hints to the presence of low copy numbers of XylR as the main reason for the bimodal responses observed in exponential phase.…”

“…Previous experimental work in yeast To and Maheshri, 2010) and bacteria (So et al, 2011) has demonstrated that transcription bursts can originate bimodal single-cell distributions without bistability. This bimodality is caused by slow promoter fluctuations between active and inactive states, and promoters with multiple binding sites/ states for activation can provide such infrequent events To and Maheshri, 2010). To elucidate if this is the case in the system under study, we examined the time course of the different species involved in the network.…”

Transcriptional activators and activation mechanisms

“…In other words, these measured products have already been averaged over many cells and, thus, depict only the "average" behavior of these cells as a group. Recent studies of evaluating the transcriptional products of individual cells suggest that transcription takes place as discrete bursts (Elowitz et al, 2002;Kaern et al, 2005;Raser and O'Shea, 2005;Golding and Cox, 2006;Pare et al, 2009;Chubb and Liverpool, 2010;To and Maheshri, 2010). Transcriptional activators appear to increase the frequency or probability of such bursts, as opposed to the number of transcripts produced per burst To and Maheshri, 2010;He et al, 2011).…”