Multiple light inputs to a simple clock circuit allow complex biological rhythms

School of Biological Sciences, University of Edinburgh and Centre for Systems Biology at Edinburgh, Edinburgh EH93JD, UK.
The Plant Journal (Impact Factor: 5.97). 04/2011; 66(2):375-85. DOI: 10.1111/j.1365-313X.2011.04489.x
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Circadian clocks are biological timekeepers that allow living cells to time their activity in anticipation of predictable environmental changes. Detailed understanding of the circadian network of higher plants, such as Arabidopsis thaliana, is hampered by the high number of partially redundant genes. However, the picoeukaryotic alga Ostreococcus tauri, which was recently shown to possess a small number of non-redundant clock genes, presents an attractive alternative target for detailed modelling of circadian clocks in the green lineage. Based on extensive time-series data from in vivo reporter gene assays, we developed a model of the Ostreococcus clock as a feedback loop between the genes TOC1 and CCA1. The model reproduces the dynamics of the transcriptional and translational reporters over a range of photoperiods. Surprisingly, the model is also able to predict the transient behaviour of the clock when the light conditions are altered. Despite the apparent simplicity of the clock circuit, it displays considerable complexity in its response to changing light conditions. Systematic screening of the effects of altered day length revealed a complex relationship between phase and photoperiod, which is also captured by the model. The complex light response is shown to stem from circadian gating of light-dependent mechanisms. This study provides insights into the contributions of light inputs to the Ostreococcus clock. The model suggests that a high number of light-dependent reactions are important for flexible timing in a circadian clock with only one feedback loop.

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    • "Diverse models have been created to simulate the circadian clock in different species (Fig. 2). Mathematical differential-equation models have been developed for mammals (Mus musculus) [14] [41] [42], insects (D. melanogaster) [43] [44] [45] [46], plants (Arabidopsis thaliana) [47] [48] [49], Ostreococcus tauri [50] [51], fungi (Neurospora crassa) [52] [53] [54], and cyanobacteria [55] [56]. So far, focus is set on modelling of the core-clock in an attempt to elucidate its characteristic properties, such as self-sustained oscillations, robustness, synchronization among cells and entrainment to external inputs. "
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    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.
    Computational and Structural Biotechnology Journal 08/2015; 13:417-26. DOI:10.1016/j.csbj.2015.07.001
    • "Both CK2 subunits are encoded by a single gene, which is very strongly related to the human and other animal homologs. The O. tauri circadian clock has been studied in some detail both in vivo [18] [19] [20] and in silico [21] [22]. Whilst the simplicity of these cells is key to the efficient study of eukaryotic signalling, it does provide a challenge to obtain sufficient material for quantitative proteomics; cells divide a maximum of once a day, are tiny, and do not grow to high densities. "
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    ABSTRACT: Casein Kinase 2 (CK2) is a protein kinase that phosphorylates a plethora of cellular target proteins involved in processes including DNA repair, cell cycle control, and circadian timekeeping. CK2 is functionally conserved across eukaryotes, although the substrate proteins identified in a range of complex tissues are often different. The marine alga Ostreococcus tauri is a unicellular eukaryotic model organism ideally suited to efficiently study generic roles of CK2 in the cellular circadian clock. Overexpression of CK2 leads to a slow circadian rhythm, verifying functional conservation of CK2 in timekeeping. The proteome was analysed in wild-type and CK2-overexpressing algae at dawn and dusk, revealing that differential abundance of the global proteome across the day is largely unaffected by overexpression. However, CK2 activity contributed more strongly to timekeeping at dusk than at dawn. The phosphoproteome of a CK2 overexpression line and cells treated with CK2 inhibitor was therefore analysed and compared to control cells at dusk. We report an extensive catalogue of 447 unique CK2-responsive differential phosphopeptide motifs to inform future studies into CK2 activity in the circadian clock of more complex tissues This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Proteomics 04/2015; DOI:10.1002/pmic.201500086 · 3.81 Impact Factor
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    • "This finding was supported further by mathematical modeling studies, which could reproduce experimental expression time-courses with great accuracy (Morant et al., 2010; Thommen et al., 2010, 2012; Troein et al., 2011; Dixon et al., 2014). Remarkably, some of these analyzes showed that the light sensing mechanisms in O. tauri is carefully designed so that the clock is robust to daylight intensity fluctuations (Thommen et al., 2010) but flexibly adapts to photoperiod changes (Thommen et al., 2012), allowing it to cope with weather and seasonal variations (Troein et al., 2009; Pfeuty et al., 2012). However, the evidence was indirect and did not specify the light input pathway components. "
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    ABSTRACT: Most organisms anticipate daily environmental variations and orchestrate cellular functions thanks to a circadian clock which entrains robustly to the day/night cycle, despite fluctuations in light intensity due to weather or seasonal variations. Marine organisms are also subjected to fluctuations in light spectral composition as their depth varies, due to differential absorption of different wavelengths by sea water. Studying how light input pathways contribute to circadian clock robustness is therefore important. Ostreococcus tauri, a unicellular picoplanktonic marine green alga with low genomic complexity and simple cellular organization, has become a promising model organism for systems biology. Functional and modeling approaches have shown that a core circadian oscillator based on orthologs of Arabidopsis TOC1 and CCA1 clock genes accounts for most experimental data acquired under a wide range of conditions. Some evidence points at putative light input pathway(s) consisting of a two-component signaling system (TCS) controlled by the only two histidine kinases (HK) of O. tauri. LOV-HK is a blue light photoreceptor under circadian control, that is required for circadian clock function. An involvement of Rhodopsin-HK (Rhod-HK) is also conceivable since rhodopsin photoreceptors mediate blue to green light input in animal circadian clocks. Here, we probe the role of LOV-HK and Rhod-HK in mediating light input to the TOC1-CCA1 oscillator using a mathematical model incorporating the TCS hypothesis. This model agrees with clock gene expression time series representative of multiple environmental conditions in blue or green light, characterizing entrainment by light/dark cycles, free-running in constant light, and resetting. Experimental and theoretical results indicate that both blue and green light can reset O. tauri circadian clock. Moreover, our mathematical analysis suggests that Rhod-HK is a blue-green light receptor and drives the clock together with LOV-HK.
    Frontiers in Genetics 02/2015; 6:65. DOI:10.3389/fgene.2015.00065
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