Systems Biology-Derived Discoveries of Intrinsic Clocks

Abstract

A systems approach to studying biology uses a variety of mathematical, computational, and engineering tools to holistically understand and model properties of cells, tissues, and organisms. Building from early biochemical, genetic, and physiological studies, systems biology became established through the development of genome-wide methods, high-throughput procedures, modern computational processing power, and bioinformatics. Here, we highlight a variety of systems approaches to the study of biological rhythms that occur with a 24-h period-circadian rhythms. We review how systems methods have helped to elucidate complex behaviors of the circadian clock including temperature compensation, rhythmicity, and robustness. Finally, we explain the contribution of systems biology to the transcription-translation feedback loop and posttranslational oscillator models of circadian rhythms and describe new technologies and "-omics" approaches to understand circadian timekeeping and neurophysiology.

Keywords: RNA sequencing; circadian rhythm; models; neurophysiology; ribosome profiling; systems biology; theory.

Figure 1

Systems approaches to studying circadian rhythms. On an organism level, researchers are using CRISPR/Cas9 and TALEN coupled with new sleep staging techniques to uncover mutations in genes that increase or decrease sleep. On a tissue level, new tissue clearing techniques such as CLARITY and CUBIC are enabling researchers to investigate the neuroanatomical basis of behavior (see Systems Neurophysiology). On a cell level, systems transcriptomics experiments have revealed not only rhythmic mRNA levels through microarrays and RNA sequencing but also other molecular details such as chromatin state, mRNA structure and modification, ribosome binding, and rhythmic protein abundance (see Systems Transcriptomics, Systems Proteomics and Metabolomics, and Systems Approaches to Study Translation Regulation in Circadian Rhythms). On a molecular level, reconstitution of a cyanobacteria posttranslational oscillator and the discovery of transcription/translation independent peroxiredoxin rhythms have expanded our understanding of circadian oscillations (see Periodicity and the Rise of the Posttranslation Circadian Oscillator). Systems modelers have discovered insights into constraints and parameters necessary for unique features of the circadian clock such as entrainment, periodicity, robustness, and temperature compensation (see Modeling the Systems Properties of Circadian Rhythms).