Transcription Factor Oscillations Induce Differential Gene Expressions

Abstract

Intracellular protein levels of diverse transcription factors (TFs) vary periodically with time. However, the effects of TF oscillations on gene expression, the primary role of TFs, are poorly understood. In this study, we determined these effects by comparing gene expression levels induced in the presence and in the absence of TF oscillations under same mean intracellular protein level of TF. For all the nonlinear TF transcription kinetics studied, an oscillatory TF is predicted to induce gene expression levels that are distinct from a nonoscillatory TF. The conditions dictating whether TF oscillations induce either higher or lower average gene expression levels were elucidated. Subsequently, the predicted effects from an oscillatory TF, which follows sigmoid transcription kinetics, were applied to demonstrate how oscillatory dynamics provide a mechanism for differential target gene transactivation. Generally, the mean TF concentration at which oscillations occur relative to the promoter binding affinity of a target gene determines whether the gene is up- or downregulated whereas the oscillation amplitude amplifies the magnitude of the differential regulation. Notably, the predicted trends of differential gene expressions induced by oscillatory NF-κB and glucocorticoid receptor match the reported experimental observations. Furthermore, the biological function of p53 oscillations is predicted to prime the cell for death upon DNA damage via differential upregulation of apoptotic genes. Lastly, given N target genes, an oscillatory TF can generate between (N-1) and (2N-1) distinct patterns of differential transactivation. This study provides insights into the mechanism for TF oscillations to induce differential gene expressions, and underscores the importance of TF oscillations in biological regulations.

Noise Facilitates Transcriptional Control under Dynamic Inputs

“…While extrinsic noise leads to differences in oscillation frequency between cells creating heterogeneous locking behavior and increases entrainment robustness of the population to changes in input period, a surprising finding is the beneficial role for intrinsic noise in dynamical signaling: molecular fluctuation arising from low copy-number feedback transcripts (IkB and A20) can act to enhance NF-kB oscillation and expand the range of inputs that entrain NF-kB and ultimately enhance target gene expression ( Figure 7). Increased gene expression was explained by incorporating data on non-linear NF-kB-DNA binding affinity into the model, and we see the greatest differential regulation for late genes such as Ccl5 in agreement with findings that late genes are more sensitive to oscillatory regulation (Ashall et al, 2009;Wee et al, 2012).…”

“…Experiments indicate that NF-kB binds DNA cooperatively with Hill coefficient $4 (Phelps et al, 2000) (Figure S2A). Introducing this non-linearity in our model created significantly increased transcriptional output for entrained versus non-entrained conditions, in agreement with our experiments ( Figures 3G and S2C) (Wee et al, 2012). Increasing intrinsic noise led to stronger oscillations and further amplified the NF-kB-induced gene expression ( Figure 3G).…”

Systems biology of cellular rhythms

“…Periodic nuclear translocation, playing a role in gene regulation, has been observed in yeast for another transcription factor, Crz1 [79]. Oscillatory translocation of transcription factors to the nucleus results in their periodic activation and could thereby govern the frequency-dependent expression of specific groups of genes [80].…”

Growth control mechanisms in neuronal regeneration

“…Although the model above‐mentioned was meant to explain how cells sense their length, similar mechanisms based on oscillatory signals might be used in injury/regeneration. Indeed, oscillations in the nuclear import of certain transcriptional factors, including Smad1 and STAT3, which play an important role in injury response as previously discussed, has been demonstrated to modulate gene expression in various biological systems [100–103]. Such a system might enable lesion sensing as a sudden change in apparent axon length, possibly through frequency encoding of importin‐mediated retrograde signals [16].…”