Abstract

The mammalian circadian clock is a cell-autonomous system that drives oscillations in behavior and physiology in anticipation of daily environmental change. To assess the robustness of a human molecular clock, we systematically depleted known clock components and observed that circadian oscillations are maintained over a wide range of disruptions. We developed a novel strategy termed Gene Dosage Network Analysis (GDNA) in which small interfering RNA (siRNA)-induced dose-dependent changes in gene expression were used to build gene association networks consistent with known biochemical constraints. The use of multiple doses powered the analysis to uncover several novel network features of the circadian clock, including proportional responses and signal propagation through interacting genetic modules. We also observed several examples where a gene is up-regulated following knockdown of its paralog, suggesting the clock network utilizes active compensatory mechanisms rather than simple redundancy to confer robustness and maintain function. We propose that these network features act in concert as a genetic buffering system to maintain clock function in the face of genetic and environmental perturbation. The circadian clock is the biological clock found throughout the body that coordinates the timing of molecular and cellular processes on a 24-hour rhythm. It is composed of numerous transcription factors that feed back and control their own expression. To explore how the clock functions in the face of genetic perturbations, we disrupted its function by knocking down gene expression of known clock genes in a dose-dependent fashion. We measured the expression of clock genes following knockdown and constructed perturbation-based network models to describe, visualize, and mine the results. We reported several novel network features, such as signal propagation through interacting genetic modules and proportional responses whereby levels of expression are altered commensurately with changing levels of the gene. We also observed several examples where a gene is up-regulated following knockdown of its paralog, suggesting the clock network utilizes active compensatory mechanisms rather than simple redundancy to confer robustness and maintain function. We propose that the network features we observe act in concert as a genetic buffering system to maintain clock function in the face of genetic and environmental perturbation.

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