Multiple transcription auto regulatory loops can act as robust oscillators and decision-making motifs

Abstract

Response time decides how fast a gene can react against an external signal at the transcription level in a signalling cascade. The steady state protein levels of the responding genes decide the coupling between two consecutive members of a signalling cascade. A negative autoregulatory loop (NARL) present in a transcription factor network can speed up the response time of the regulated gene at the cost of reduced steady state protein level. We present here a multi NARL motif which can be tuned for both the steady state protein level as well as response time in the required direction. Remarkably, there exists an optimum Hill coefficient nopt≅4 at which the response time of the NARL motif is at minimum. When the Hill coefficient is n < nopt, then under strong binding conditions, one can raise the steady state protein level by increasing the gene copy number with almost no change in the response time of the multi NARL motif. Using detailed computational analysis, we show that the coupled multi NARL and positive auto regulatory loop (PARL) motifs can act as an oscillator as well as decision making component which are robust against extrinsic fluctuations in the control parameters. We further demonstrate that the period of oscillation of the coupled multi NARL-PARL dual feedback oscillator can also be fine-tuned by the gene copy number apart from the inducer concentration. We finally demonstrate robustness of bistable dual feedback decision making motifs with multi autoregulatory loop component.