Clocks not winding down: unravelling circadian networks

Zhang, Eric Erquan; Kay, Steve A.

doi:10.1038/nrm2995

Cited by 393 publications

(372 citation statements)

References 113 publications

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“…In biomolecular regulatory networks, oscillatory systems control many vital functions, including circadian rhythms (Zhang and Kay 2010), glycolysis (Chandra et al 2011), DNA damage response (Batchelor et al 2008), among others (Tiana et al 2007). Given this ubiquitousness, it is no surprise that oscillatory systems have been extensively studied for a long time ).…”

Section: Introductionmentioning

confidence: 99%

Design principles for robust oscillatory behavior

2015

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Oscillatory responses are ubiquitous in regulatory networks of living organisms, a fact that has led to extensive efforts to study and replicate the circuits involved. However, to date, design principles that underlie the robustness of natural oscillators are not completely known. Here we study a three-component enzymatic network model in order to determine the topological requirements for robust oscillation. First, by simulating every possible topological arrangement and varying their parameter values, we demonstrate that robust oscillators can be obtained by augmenting the number of both negative feedback loops and positive autoregulations while maintaining an appropriate balance of positive and negative interactions. We then identify network motifs, whose presence in more complex topologies is a necessary condition for obtaining oscillatory responses. Finally, we pinpoint a series of simple architectural patterns that progressively render more robust oscillators. Together, these findings can help in the design of more reliable synthetic biomolecular networks and may also have implications in the understanding of other oscillatory systems.

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Section: Introductionmentioning

confidence: 99%

Design principles for robust oscillatory behavior

2015

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“…(A) The sketch of the transcription--translation feedback loop hypothesis advanced by Hardin et al in 1990. (B) A much more filled in account of the clock mechanism schema presented by Zhang and Kay (2010) to reflect the conception of the clock mechanism that had been advanced by 2005. The originally identified feedback loop involving PER is shown in the upper right, with the addition that PER forms a dimer with CRY, generated through a similar feedback loop.…”

Section: Decomposing and Recomposing An Intracellular Circadian Mechamentioning

confidence: 99%

Mechanists Must be Holists Too! Perspectives from Circadian Biology

Bechtel

2016

J Hist Biol

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The pursuit of mechanistic explanations in biology has produced a great deal of knowledge about the parts, operations, and organization of mechanisms taken to be responsible for biological phenomena. Holist critics have often raised important criticisms of proposed mechanistic explanations, but until recently holists have not had alternative research strategies through which to advance explanations. This paper argues both that the results of mechanistic strategies has forced mechanists to confront ways in which whole systems affect their components and that new representational and modeling strategies are providing tools for understanding these effects of whole systems upon components. Drawing from research on the mechanism responsible for circadian rhythms in mammals, I develop two examples in which mechanistic analysis is being integrated into a more holist perspective: research revealing intercellular integration of circadian mechanisms with those involved in cell metabolism and research revealing that stable rhythms are dependent on how individual cells in the suprachiasmatic nucleus synchronize with each other to generate regular rhythms. Tools such as network diagramming and computational modeling are providing means to integrate mechanistic models into accounts of whole systems.

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“…10,14 The best-characterized loop and the first to be identified, the central, or core loop is comprised of two morning-expressed Myb transcription factors, CIRCADIANCLOCK-ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY ), and an evening-expressed gene, TIMING OF CAB EXPRESSION1 (TOC1). In this loop, the morning expression and functional redundancy of CCA1/LHY represses the expression of TOC1 by directly binding to Evening Elements in the TOC1 promoter region, which make up the negative arm of the core loop in Arabidopsis.…”

Section: Repressive Activity Of Toc1 In Regulating the Clockmentioning

confidence: 99%

“…3,6,7 Correct matching of the periodicity of the endogenous circadian clock with local day/ night cycles enhances growth and survival, and confers advantages in terms of fitness to higher plants. 4,[8][9][10] The molecular architecture of the circadian clock in most organisms consists of multiple, interlocked regulatory loops that are responsible for integrating input and generating overt The circadian clock is an endogenous timing system responsible for coordinating an organism's biological processes with its environment. Interlocked transcriptional feedback loops constitute the fundamental architecture of the circadian clock.…”

Section: Introductionmentioning

confidence: 99%