Catching transcriptional regulation by thermostatistical modeling

Frank, T. D.; Cheong, Alex; Okada‐Hatakeyama, Mariko; Kholodenko, Boris N.

doi:10.1088/1478-3975/9/4/045007

Cited by 8 publications

(7 citation statements)

References 42 publications

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“…Thereby expression is restricted to the pericentral zone of a liver lobule where β-catenin levels are high. This behavior closely resembles a logical AND gate, which has been widely discussed in recent literature ( 37 , 39 , 40 , 67 , 68 ). It is interesting to see that the apparent AND-gate logic of the CYP1A1 promoter is established not only by interactions between the cis -regulatory binding sites, but in addition also by the interaction between Wnt/β-catenin and AhR signaling pathways.…”

Section: Resultssupporting

confidence: 58%

Signal integration by the CYP1A1 promoter -- a quantitative study

Schulthess

Löffler

Vetter

et al. 2015

Nucleic Acids Research

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Genes involved in detoxification of foreign compounds exhibit complex spatiotemporal expression patterns in liver. Cytochrome P450 1A1 (CYP1A1), for example, is restricted to the pericentral region of liver lobules in response to the interplay between aryl hydrocarbon receptor (AhR) and Wnt/β-catenin signaling pathways. However, the mechanisms by which the two pathways orchestrate gene expression are still poorly understood. With the help of 29 mutant constructs of the human CYP1A1 promoter and a mathematical model that combines Wnt/β-catenin and AhR signaling with the statistical mechanics of the promoter, we systematically quantified the regulatory influence of different transcription factor binding sites on gene induction within the promoter. The model unveils how different binding sites cooperate and how they establish the promoter logic; it quantitatively predicts two-dimensional stimulus-response curves. Furthermore, it shows that crosstalk between Wnt/β-catenin and AhR signaling is crucial to understand the complex zonated expression patterns found in liver lobules. This study exemplifies how statistical mechanical modeling together with combinatorial reporter assays has the capacity to disentangle the promoter logic that establishes physiological gene expression patterns.

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Section: Resultssupporting

confidence: 58%

Signal integration by the CYP1A1 promoter -- a quantitative study

Schulthess

Löffler

Vetter

et al. 2015

Nucleic Acids Research

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“…To this end, the transcriptional activity parameter is considered as a function of the transcription factor concentrations. Explicit models, for example, using a thermostatistical approach have been proposed for that purpose (see [4,36] and references therein). Unknown parameters of such thermostatistical models or functional dependencies between and transcription factor concentrations can be estimated when (in replacement for ) is estimated for dose responses of the set of transcription factors of interest.…”

Section: Discussionmentioning

confidence: 99%

“…Stochastic accounts, for example, based on chemical Langevin equations, provide a mathematical framework to address both the deterministic and stochastic components of promoter activity [2]. In the literature, modeling of gene transcription often starts at the promoter level with the transcription event [3][4][5][6]. Accordingly, mRNA is produced at a certain rate .…”

Section: Introductionmentioning

confidence: 99%

Effective Single-Step Posttranscriptional Dynamics Allowing for a Direct Maximum Likelihood Estimation of Transcriptional Activity and the Quantification of Sources of Gene Expression Variability with an Illustration for the Hypoxia and TNFαRegulated Inflammatory Pathway

Frank

Collins

Cheong

2013

ISRN Computational Biology

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Data analysis methods for estimating promoter activity from gene reporter data frequently involve the reconstruction of the dynamics of unobserved species and numerical search algorithms for determining optimal model parameters. In contrast, we argue that posttranscriptional dynamics effectively behave like a singlestep stochastic process when gene expression variability is relatively low and, half-lives of the unobserved species are relatively small compared to characteristic observation time scales. In this case, by means of maximum likelihood estimators, for which analytical expressions exist, transcriptional activity of gene promoters can be estimated directly from observed gene reporter data without the need for numerical search algorithms and the reconstruction of unobserved variables. In addition, the model-based data analysis approach yields a single variable that measures the effective strength of the sources that give rise to gene expression variability. The approach is applied to conduct a model-based analysis of the inflammatory pathway under hypoxia condition and stimulation with tumor necrosis factor alpha in HEK293 cells.

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“…Thus, a dimensionless, relative concentration variable [TF] rel is obtained [ 25 ]. For the 1-site model and for the AND gate, the transcriptional activity as a function of [TF] rel reads as [ 26 ]. with exponents n = 1 for the 1-site model and n = 2 for the AND gate.…”

Section: Methodsmentioning

confidence: 99%

Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate

Nguyen

Cavadas

Kholodenko

et al. 2015

Cell. Mol. Life Sci.

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Cyclooxygenase 2 (COX2), a key regulatory enzyme of the prostaglandin/eicosanoid pathway, is an important target for anti-inflammatory therapy. It is highly induced by pro-inflammatory cytokines in a Nuclear factor kappa B (NFκB)-dependent manner. However, the mechanisms determining the amplitude and dynamics of this important pro-inflammatory event are poorly understood. Furthermore, there is significant difference between human and mouse COX2 expression in response to the inflammatory stimulus tumor necrosis factor alpha (TNFα). Here, we report the presence of a molecular logic AND gate composed of two NFκB response elements (NREs) which controls the expression of human COX2 in a switch-like manner. Combining quantitative kinetic modeling and thermostatistical analysis followed by experimental validation in iterative cycles, we show that the human COX2 expression machinery regulated by NFκB displays features of a logic AND gate. We propose that this provides a digital, noise-filtering mechanism for a tighter control of expression in response to TNFα, such that a threshold level of NFκB activation is required before the promoter becomes active and initiates transcription. This NFκB-regulated AND gate is absent in the mouse COX2 promoter, most likely contributing to its differential graded response in promoter activity and protein expression to TNFα. Our data suggest that the NFκB-regulated AND gate acts as a novel mechanism for controlling the expression of human COX2 to TNFα, and its absence in the mouse COX2 provides the foundation for further studies on understanding species-specific differential gene regulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-015-1850-1) contains supplementary material, which is available to authorized users.

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Catching transcriptional regulation by thermostatistical modeling

Cited by 8 publications

References 42 publications

Signal integration by the CYP1A1 promoter -- a quantitative study

Signal integration by the CYP1A1 promoter -- a quantitative study

Effective Single-Step Posttranscriptional Dynamics Allowing for a Direct Maximum Likelihood Estimation of Transcriptional Activity and the Quantification of Sources of Gene Expression Variability with an Illustration for the Hypoxia and TNFαRegulated Inflammatory Pathway

Species differential regulation of COX2 can be described by an NFκB-dependent logic AND gate

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