Daily rhythms are a constant part of life. This special Focus issue explores the molecular mechanisms that underlie the generation of circadian dynamics.
Our world is constantly changing, from day–night and seasonal cycles to more local environmental variations. Organisms must adapt their physiology and behavior to these changes to ensure survival. At the cellular level, this adaptation is achieved by molecular oscillators, which are present in virtually all cells and allow organisms to anticipate and adjust to fluctuations within their environments. This capability is especially apparent in circadian rhythms, oscillations that have a period of approximately 24 hours.
The circadian clock is a cell-autonomous oscillator that generates and sustains an endogenous 24-hour period whose timing can be synchronized to external cues, such as light–dark or feeding–fasting cycles. Thus, the clock coordinates regular patterns of eating, sleeping and activity. Loss of synchrony between the internal circadian rhythms and environmental day–night timing is responsible for jet lag and seasonal affective disorder. In addition, the recent rise in human diseases linked to lifestyles without regular patterns of sleeping and eating emphasizes the need to understand how internal rhythms are generated and are entrained to external cycles.
In this issue, we present a special Focus on Cycles and Rhythms (http://www.nature.com/nsmb/focus/cycles_and_rhythms) that discusses insights into the molecular mechanisms of oscillator function and the central roles they play in metabolic and circadian regulation.
The regulatory mechanisms that drive oscillatory behavior are diverse and often complex. Nevertheless, as Cao, Lopatkin and You discuss in their Perspective, there are five distinct design elements that are critical in generating oscillations in time and space: negative and positive feedback; time delay; nonlinearity in regulation; and random fluctuations ('noise'). How these basic elements combine and generate complex patterns is still poorly understood, but reduction of the complexity to a combination of these elements should aid in the analysis and interpretation of biological oscillations and in defining the roles of specific molecular components.
The yeast metabolic cycle (YMC) is the first example of cyclic behavior highlighted in this Focus issue. The YMC also relates to circadian rhythms; in fact, it has been proposed that circadian rhythms can be regarded as metabolic cycles with time-keeping mechanisms. A Review by Mellor discusses how in Saccharomyces cerevisiae oxidative and reductive phases of metabolism are divided through oscillating phases of gene expression and post-transcriptional modifications. This temporal compartmentalization ensures that incompatible processes, such as anabolic and catabolic metabolism, do not occur simultaneously, thus avoiding a waste of energy. The molecular basis for this oscillatory behavior involves an intricate interplay of transcription regulators, transcriptional interference and chromatin modifications, all of which are linked and driven by environmental changes.
The molecular engine of the circadian clock is a transcription- and translation-based negative feedback loop that drives rhythmic protein synthesis and degradation, thereby generating an endogenous 24-hour cycle. The mechanisms underlying circadian transcriptional regulation in mammalian cells are examined in a Review by Papazyan, Zhang and Lazar. The authors discuss recent insights from genome-wide analyses and biochemical studies elucidating how physical and functional interactions of core clock transcription factors at their cognate DNA regulatory elements confer rhythmic clock-gene expression. They further consider how transcriptional output is modulated by chromatin structure and histone-modifying enzymes, some of which are directly recruited to circadian gene targets by core clock proteins.
Although transcriptional regulation is central to organizing the circadian feedback loop, core clock proteins are also controlled by multiple post-translational modifications (PTMs) that modulate the levels, localization and activity of these proteins. The importance of PTMs in circadian timing is underscored by the observation that mutations that prevent normal modification of human clock proteins give rise to circadian disorders, including familial advanced sleep phase (FASP), and disturb circadian cycles in animal models. Hirano, Fu and Ptáček review and discuss the effects of phosphorylation, ubiquitination, SUMOylation, acetylation and O-GlcNAcylation on mammalian core clock factors and illustrate how opposing effects of PTMs that compete for common target residues provide a means to link the circadian clock to cellular metabolism.
The sessile nature of plants places unique demands on their ability to anticipate environmental changes occurring both daily and seasonally, and requires simultaneous environmental cues to be integrated to synchronize endogenous cellular clocks. In their Review, Nohales and Kay describe how light and temperature signals alter circadian period length by influencing transcriptional, post-transcriptional and post-translational functions of the core oscillator of Arabidopsis thaliana, thereby permitting physiological processes such as flowering, hormone signaling, growth and metabolism to be aligned with diurnal and seasonal rhythms.
Recent progress in understanding how cells generate internal cyclic rhythms has illuminated the complexity of molecular mechanisms underlying circadian timekeepers, and points of intersection between circadian regulatory loops and additional metabolic and light–dark cycles are beginning to be defined. Future work aimed at exploring how internal and external cycles are functionally intertwined should ultimately reveal how circadian clocks both sense and respond to environmental cues. These outstanding questions will challenge the field for years to come, and we look forward to seeing those developments in the pages of Nature Structural & Molecular Biology.
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Keeping time. Nat Struct Mol Biol 23, 1029 (2016). https://doi.org/10.1038/nsmb.3341