Promoter methylation in a mixed feedback loop circadian clock model

We introduce and analyze an extension of the mixed feedback loop model of François and Hakim. Our extension includes an additional promoter state and allows for reversible protein sequestration, which was absent from the original studies of the mixed feedback loop model. Motivated by experimental observations that link DNA methylation with circadian gene expression, we use our extended model to investigate the role of DNA methylation(s) in the mammalian circadian clock. We extend the perturbation analysis of François and Hakim to determine how methylation affects the presence and the periodicity of oscillations. We derive a modified Goodwin oscillator model as an approximation to show that although methylation contributes to period control, excessive methylation can abolish rhythmicity.

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