Mathematical Model of a Telomerase Transcriptional Regulatory Network Developed by Cell-Based Screening: Analysis of Inhibitor Effects and Telomerase Expression Mechanisms
Figure 4
Simulated effects of GSK3 inhibition and network noise on TERT transcription.
(A), Effect of BIO on the transcription factor promoter panel and simulation in the model. Top panel: A2780 cells were transfected with each luciferase reporter. 32 h later transfectants were treated for 16 h prior to luciferase assay with DMSO or 5 µM BIO. Luciferase assay results meeting model cut-off of FC>1.5, p<0.01 (Fos and STAT3) were modelled as rule table modifications. Lower panel: heat-map representation of new steady states obtained by setting Fos to be constitutively suppressed and STAT3 to be constitutively active. Red colour indicates the node is on, green colour indicates the node is off. (B), noise simulation by the bit-flip method under basal or BIO modified rules in the model. State coherence [73] of each attractor under the model basal rule-set (top) or BIO simulation (bottom) was evaluated as described in the text. Heat-maps of both attractors under either rule-set are shown, with colouration as above. Horizontal arrows between attractor states indicate that a transient state change of the adjacent node caused a shift to the alternate steady state. Vertical and diagonal arrows indicate the state changes resulting from the rule-set change (basal → BIO, or the reverse).