Circadian systems biology: When time matters

Abstract

The circadian clock is a powerful endogenous timing system, which allows organisms to fine-tune their physiology and behaviour to the geophysical time. The interplay of a distinct set of core-clock genes and proteins generates oscillations in expression of output target genes which temporally regulate numerous molecular and cellular processes. The study of the circadian timing at the organismal as well as at the cellular level outlines the field of chronobiology, which has been highly interdisciplinary ever since its origins. The development of high-throughput approaches enables the study of the clock at a systems level. In addition to experimental approaches, computational clock models exist which allow the analysis of rhythmic properties of the clock network. Such mathematical models aid mechanistic understanding and can be used to predict outcomes of distinct perturbations in clock components, thereby generating new hypotheses regarding the putative function of particular clock genes. Perturbations in the circadian timing system are linked to numerous molecular dysfunctions and may result in severe pathologies including cancer. A comprehensive knowledge regarding the mechanistic of the circadian system is crucial to develop new procedures to investigate pathologies associated with a deregulated clock. In this manuscript we review the combination of experimental methodologies, bioinformatics and theoretical models that have been essential to explore this remarkable timing-system. Such an integrative and interdisciplinary approach may provide new strategies with regard to chronotherapeutic treatment and new insights concerning the restoration of the circadian timing in clock-associated diseases.

Keywords: Cancer; Chronobiology; Circadian clock; Mathematical modelling.

Fig. 1

Circadian systems biology. The circadian clock is present in a large variety of organisms from simple unicellular organisms to complex mammalian systems. In mammals, a main pacemaker is located in the SCN, and peripheral clocks exist in each organ which regulate the timing of physiological processes. In fact, every single cell has its own clock and all these individual clocks are synchronized and entrained to signals received from the main pacemaker. At the cellular level the complex—CLOCK/BMAL—regulates a set of positive (green) and negative (orange) interactions which form feedback-loops. These feedback-loops are accountable for the generation of oscillations in gene expression.

Fig. 2

Measuring circadian rhythms. The oscillatory output of a model system can be observed in experimental models and simulated using computational approaches. Experimentally, different sorts of data may be produced to quantify circadian rhythms, depending on the question addressed and model used. These include, for example, actograms, bioluminescence live-cell recordings, RT-qPCR, microarray and western blot data. Also computationally, different methods are available to investigate the circadian system, mostly based on ordinary differential equations (ODEs). By means of bioinformatics approaches the analysis of experimental data and also the integration of experimental and computational data can be carried out. The interdisciplinary nature of circadian research is here once more present.