Nonlinearity arising from noncooperative transcription factor binding enhances negative feedback and promotes genetic oscillations

TL;DR

This study demonstrates that multiple noncooperative transcription factor binding sites increase feedback nonlinearity, thereby enhancing genetic oscillations, with potential implications for gene regulation mechanisms like the zebrafish segmentation clock.

Contribution

It reveals how noncooperative binding site multiplicity enhances feedback nonlinearity and oscillatory behavior in genetic systems, a novel insight into gene regulation dynamics.

Findings

Increased number of binding sites raises feedback nonlinearity.

Enhanced nonlinearity leads to larger amplitude oscillations.

Optimal configurations maximize oscillatory range.

Abstract

We study the effects of multiple binding sites in the promoter of a genetic oscillator. We evaluate the regulatory function of a promoter with multiple binding sites in the absence of cooperative binding, and consider different hypotheses for how the number of bound repressors affects transcription rate. Effective Hill exponents of the resulting regulatory functions reveal an increase in the nonlinearity of the feedback with the number of binding sites. We identify optimal configurations that maximize the nonlinearity of the feedback. We use a generic model of a biochemical oscillator to show that this increased nonlinearity is reflected in enhanced oscillations, with larger amplitudes over wider oscillatory ranges. Although the study is motivated by genetic oscillations in the zebrafish segmentation clock, our findings may reveal a general principle for gene regulation.