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 , 1/ 1800 , 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

Metadata information

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

Curation status
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 67.44 KB Preview | Download

Additional files

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: Oct 29, 2019 10:59:54 AM
  • Last Modified: Oct 29, 2019 10:59:54 AM
Revisions
  • 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
Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
REV

P20393
110.0 item
DBP

Q10586
1.0 item
E4BP4

PR:000011176
80.0 item
CRY

PR:000050151
1.0 item
PER

PR:000012548
25.0 item
Reactions
Reactions Rate Parameters
(REV) => ()

([P20393]) => ()
compartment*gamma_rev*REV

compartment*gamma_rev*[P20393]
gamma_rev = 0.241
() => (DBP)

() => ([Q10586])
compartment*E_box

compartment*E_box
E_box = 0.140122086570477
(DBP) => ()

([Q10586]) => ()
compartment*gamma_db*DBP

compartment*gamma_db*[Q10586]
gamma_db = 0.156
() => (E4BP4 + CRY)

() => ([PR:000011176] + [PR:000050151])
compartment*2*R_box

compartment*2*R_box
R_box = 3.3887906702538
(E4BP4) => ()

([PR:000011176]) => ()
compartment*gamma_E4*E4BP4

compartment*gamma_E4*[PR:000011176]
gamma_E4 = 0.295
() => (CRY)

() => ([PR:000050151])
compartment*E_box

compartment*E_box
E_box = 0.140122086570477
(PER + CRY) => (PERCRY)

([PR:000012548] + [PR:000050151]) => ([PR:000012548; PR:000050151])
compartment*gamma_pc*PER*CRY

compartment*gamma_pc*[PR:000012548]*[PR:000050151]
gamma_pc = 0.191
(PERCRY) => (PER + CRY)

([PR:000012548; PR:000050151]) => ([PR:000012548] + [PR:000050151])
compartment*gamma_cp*PERCRY

compartment*gamma_cp*[PR:000012548; PR:000050151]
gamma_cp = 0.141
(CRY) => ()

([PR:000050151]) => ()
compartment*gamma_c*CRY

compartment*gamma_c*[PR:000050151]
gamma_c = 2.34
() => (PER)

() => ([PR:000012548])
compartment*D_box

compartment*D_box
D_box = 17.3257229391434
(PER) => ()

([PR:000012548]) => ()
compartment*gamma_p*PER

compartment*gamma_p*[PR:000012548]
gamma_p = 0.844
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).