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

  public model
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
Krishna Kumar Tiwari, Johannes Meyer

Metadata information

hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
Gene Ontology circadian rhythm
isDescribedBy

Curation status
Non-curated


Tags
Name Description Size Actions

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 67.55 KB Preview | Download

Additional files

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
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

  • Model originally submitted by : Johannes Meyer
  • Submitted: Oct 29, 2019 10:59:54 AM
  • Last Modified: Feb 16, 2021 2:19:37 PM
Revisions
  • Version: 3 public model Download this version
    • Submitted on: Feb 16, 2021 2:19:37 PM
    • Submitted by: Krishna Kumar Tiwari
    • With comment: Corrected publication year for the model
  • Version: 2 public model Download this version
    • Submitted on: Oct 29, 2019 10:59:54 AM
    • Submitted by: Johannes Meyer
    • With comment: Automatically added model identifier BIOMD0000000839

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
BMAL1

Aryl hydrocarbon receptor nuclear translocator-like protein 1
1.0 item
ROR

C29881
1.0 item
DBP

Q10586
1.0 item
E4BP4

PR:000011176
80.0 item
CRY

PR:000050151
1.0 item
PER

PR:000012548
25.0 item
PERCRY

PR:000012548; PR:000050151
0.0 item
Reactions
Reactions Rate Parameters
BMAL1 => ; PERCRY compartment*gamma_bp*BMAL1*PERCRY gamma_bp = 2.58
=> ROR compartment*E_box E_box = 0.140122086570477
ROR => compartment*gamma_ror*ROR gamma_ror = 2.55
=> DBP compartment*E_box E_box = 0.140122086570477
=> E4BP4 + CRY compartment*2*R_box R_box = 3.3887906702538
E4BP4 => compartment*gamma_E4*E4BP4 gamma_E4 = 0.295
=> CRY compartment*E_box E_box = 0.140122086570477
PER + CRY => PERCRY compartment*gamma_pc*PER*CRY gamma_pc = 0.191
=> PER compartment*D_box D_box = 17.3257229391434
PER => compartment*gamma_p*PER gamma_p = 0.844
PERCRY => PER + CRY compartment*gamma_cp*PERCRY gamma_cp = 0.141
PERCRY => ; BMAL1 compartment*gamma_bp*BMAL1*PERCRY gamma_bp = 2.58
=> BMAL1 compartment*R_box R_box = 3.3887906702538
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).