Encoding four gene expression programs in the activation dynamics of a single transcription factor

Abstract

Cellular signaling response pathways often exhibit a bow-tie topology [1,2]: multiple upstream stress signals converge on a single shared transcription factor, which is thought to induce different downstream gene expression programs (Figure 1A). However, if several different signals activate the same transcription factor, can each signal then induce a specific gene expression response? A growing body of literature supports a temporal coding theory where information about environmental signals can be encoded, at least partially, in the temporal dynamics of the shared transcription factor [1,2]. For example, in the case of the budding yeast transcription factor Msn2, different stresses induce distinct Msn2 activation dynamics: Msn2 shows pulsatile nuclear activation with dose-dependent frequency under glucose limitation, but sustained nuclear activation with dose-dependent amplitude under oxidative stress [3]. These dynamic patterns can then lead to differential gene expression responses [3-5], but it is not known how much specificity can be obtained. Thus, a major question of this temporal coding theory is how many gene response programs or cellular functions can be robustly encoded by dynamic control of a single transcription factor. Here we provide the first direct evidence that, simply by regulating the activation dynamics of a single transcription factor, it is possible to preferentially induce four distinct gene expression programs.

Dynamic Ligand Discrimination in the Notch Signaling Pathway

“…The use of dynamics to transmit multiple signals through the same pathway occurs in other systems (Purvis and Lahav, 2013) including p53 (Batchelor et al, 2011; Purvis et al, 2012), NFAT (Noren et al, 2016; Yissachar et al, 2013), nuclear factor κB (NF-κB) (Cheong et al, 2008; Covert et al, 2005), growth factor signaling (Marshall, 1995; Santos et al, 2007), and yeast stress response (Hansen and O’Shea, 2016; Hao and O’Shea, 2011), suggesting it is a broadly useful strategy. Dynamic encoding could be particularly beneficial when the amplitude of signaling is difficult to control precisely, due to variability in expression or cell contact.…”

Encoding Growth Factor Identity in the Temporal Dynamics of FOXO3 under the Combinatorial Control of ERK and AKT Kinases

“…Relocalization plays an important role in the regulation of transcription factors and has recently been shown by live cell imaging to involve pulses of active and inactive states. In the case of mammalian transcription factors such as NF-kB and p53 (Batchelor et al, 2008; Tay et al, 2010) and yeast Msn2 and Crz1 (Cai et al, 2008; Hao and O’Shea, 2011), modulation of the timing and duration of nuclear-cytosolic translocation carries information about the strength and identity of the initiating stimulus (Hansen and O’Shea, 2016; Tay et al, 2010). We build on these concepts by demonstrating that FoxO3 dynamics comprise early and late phases that respond independently to differences in the relative activities of ERK and Akt kinases, which are determined in turn by growth factor identity and concentration (all data are available for reanalysis in an NIH LINCS format at http://lincs.hms.harvard.edu/sampattavanich-cellsyst-2018/).…”

p53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics

“…Another potential level of regulation is through the temporal dynamics of transcription factors. Indeed, recent single cell studies pointed to a few examples in which the dynamics of transcription factors differ for different stimuli 5–7 and lead to distinct gene expression and phenotypic responses 3,8,9 . Understanding the molecular mechanisms that detect time-dependent features of transcription factors, and decode them into distinct gene expression profiles, remains a challenge.…”