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## Almeida2019 - Transcription-based circadian mechanism controls the duration of molecular clock states in response to signaling inputs

Model Identifier
BIOMD0000000839
Short description
This is a transcriptional-based mathematical model centered on linear combinations of the clock controlled elements (CCEs): E-box, R-box and D-box, used to identify the essential interactions needed to generate phase opposition between the activating CLOCK:BMAL1 and the repressing PER:CRY complexes.
Format
SBML (L2V4)
Related Publication
• Transcription-based circadian mechanism controls the duration of molecular clock states in response to signaling inputs.
• Almeida S, Chaves M, Delaunay F
• Journal of theoretical biology , 9/ 2019 , Volume 484 , pages: 110015 , PubMed ID: 31539528
• 1600 Université Côte d'Azur, Inria, INRA, CNRS, UPMC Univ Paris 06, Biocore team, Sophia Antipolis, France; Université Côte d'Azur, CNRS, INSERM, iBV, France. Electronic address: sofia.figueiredo-almeida@inria.fr.
• The molecular oscillator of the mammalian circadian clock consists in a dynamical network of genes and proteins whose main regulatory mechanisms occur at the transcriptional level. From a dynamical point of view, the mechanisms leading to an oscillatory solution with an orderly protein peak expression and a clear day/night phase distinction remain unclear. Our goal is to identify the essential interactions needed to generate phase opposition between the activating CLOCK:BMAL1 and the repressing PER:CRY complexes and to better distinguish these two main clock molecular phases relating to rest/activity and fast/feeding cycles. To do this, we develop a transcription-based mathematical model centered on linear combinations of the clock controlled elements (CCEs): E-box, R-box and D-box. Each CCE is responsive to activators and repressors. After model calibration with single-cell data, we explore entrainment and period tuning via interplay with metabolism. Variation of the PER degradation rate γp, relating to the tau mutation, results in asymmetric changes in the duration of the different clock molecular phases. Time spent at the state of high PER/PER:CRY decreases with γp, while time spent at the state of high BMAL1 and CRY1, both proteins with activity in promoting insulin sensitivity, remains constant. This result suggests a possible mechanism behind the altered metabolism of tau mutation animals. Furthermore, we expose the clock system to two regulatory inputs, one relating to the fast/feeding cycle and the other to the light-dependent synchronization signaling. We observe the phase difference between these signals to also affect the relative duration of molecular clock states. Simulated circadian misalignment, known to correlate with insulin resistance, leads to decreased duration of BMAL1 expression. Our results reveal a possible mechanism for clock-controlled metabolic homeostasis, whereby the circadian clock controls the relative duration of different molecular (and metabolic) states in response to signaling inputs.
Contributors
Johannes Meyer, Krishna Kumar Tiwari

Curation status
Curated

Modelling approach(es)

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### Model files

Almeida2019.xml SBML L2V4 Representation of Almeida2019 - Transcription-based circadian mechanism controls the duration of molecular clock states in response to signaling inputs 67.44 KB Preview | Download

Almeida2019.cps COPASI file of Almeida2019 - Transcription-based circadian mechanism controls the duration of molecular clock states in response to signaling inputs 108.27 KB Preview | Download
Almeida2019.sedml SED-ML file of Almeida2019 - Transcription-based circadian mechanism controls the duration of molecular clock states in response to signaling inputs 5.32 KB Preview | Download
• Model originally submitted by : Johannes Meyer
• Submitted: 29-Oct-2019 10:59:54
##### Revisions
• Version: 3
• Submitted on: 16-Feb-2021 14:19:37
• Submitted by: Krishna Kumar Tiwari
• With comment: Corrected publication year for the model
• Version: 2
• Submitted on: 29-Oct-2019 10:59:54
• Submitted by: Johannes Meyer
• With comment: Automatically added model identifier BIOMD0000000839

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Curator's comment:
(added: 29 Oct 2019, 10:59:41, updated: 29 Oct 2019, 10:59:41)
Reproduced plot of Figure 2 in the original publication. Curves for t < 150 are included. Model simulated and plot produced using COPASI 4.24 (Build 197).