Dynamic patterns of gene regulation I: simple two-gene systems.

Regulation of gene activities is studied by means of computer assisted mathematical analysis of ordinary differential equations (ODEs) derived from binding equilibria and chemical reaction kinetics. Here, we present results on cross-regulation of two genes through activator and/or repressor binding. Arbitrary (differentiable) binding function can be used but systematic investigations are presented for gene-regulator complexes with integer valued Hill coefficients up to n=4. The dynamics of gene regulation is derived from bifurcation patterns of the underlying systems of kinetic ODEs. In particular, we present analytical expressions for the parameter values at which one-dimensional (transcritical, saddle-node or pitchfork) and/or two-dimensional (Hopf) bifurcations occur. A classification of regulatory states is introduced, which makes use of the sign of a 'regulatory determinant'D (being the determinant of the block in the Jacobian matrix that contains the derivatives of the regulator binding functions): (i) systems with D<0, observed, for example, if both proteins are activators or repressors, to give rise to one-dimensional bifurcations only and lead to bistability for n>or=2 and (ii) systems with D>0, found for combinations of activation and repression, sustain a Hopf bifurcation and undamped oscillations for n>2. The influence of basal transcription activity on the bifurcation patterns is described. Binding of multiple subunits can lead to richer dynamics than pure activation or repression states if intermediates between the unbound state and the fully saturated DNA initiate transcription. Then, the regulatory determinant D can adopt both signs, plus and minus.