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Dynamical Principles of Two-Component Genetic Oscillators
Genetic oscillators based on the interaction of a small set of molecular components have been shown to be involved in the regulation of the cell cycle, the circadian rhythms, or the response of several signaling pathways. Uncovering the functional properties of such oscillators then becomes important for the understanding of these cellular processes and for the characterization of fundamental properties of more complex clocks. Here, we show how the dynamics of a minimal two-component oscillator is drastically affected by its genetic implementation. We consider a repressor and activator element combined in a simple logical motif. While activation is always exerted at the transcriptional level, repression is alternatively operating at the transcriptional (Design I) or post-translational (Design II) level. These designs display differences on basic oscillatory features and on their behavior with respect to molecular noise or entrainment by periodic signals. In particular, Design I induces oscillations with large activator amplitudes and arbitrarily small frequencies, and acts as an âintegratorâ of external stimuli, while Design II shows emergence of oscillations with finite, and less variable, frequencies and smaller amplitudes, and detects better frequency-encoded signals (âresonatorâ). Similar types of stimulus response are observed in neurons, and thus this work enables us to connect very different biological contexts. These dynamical principles are relevant for the characterization of the physiological roles of simple oscillator motifs, the understanding of core machineries of complex clocks, and the bio-engineering of synthetic oscillatory circuits
Mammalian Brain As a Network of Networks
Acknowledgements AZ, SG and AL acknowledge support from the Russian Science Foundation (16-12-00077). Authors thank T. Kuznetsova for Fig. 6.Peer reviewedPublisher PD
A population-based microbial oscillator
Genetic oscillators are a major theme of interest in the emerging field of
synthetic biology. Until recently, most work has been carried out using
intra-cellular oscillators, but this approach restricts the broader
applicability of such systems. Motivated by a desire to develop large-scale,
spatially-distributed cell-based computational systems, we present an initial
design for a population-level oscillator which uses three different bacterial
strains. Our system is based on the client-server model familiar to computer
science, and uses quorum sensing for communication between nodes. We present
the results of extensive in silico simulation tests, which confirm that our
design is both feasible and robust.Comment: Submitte
Theory on the Dynamics of Oscillatory Loops in the Transcription Factor Networks
We develop a detailed theoretical framework for various types of
transcription factor gene oscillators. We further demonstrate that one can
build genetic-oscillators which are tunable and robust against perturbations in
the critical control parameters by coupling two or more independent
Goodwin-Griffith oscillators through either -OR- or -AND- type logic. Most of
the coupled oscillators constructed in the literature so far seem to be of -OR-
type. When there are transient perturbations in one of the -OR- type
coupled-oscillators, then the overall period of the system remains constant
(period-buffering) whereas in case of -AND- type coupling the overall period of
the system moves towards the perturbed oscillator. Though there is a
period-buffering, the amplitudes of oscillators coupled through -OR- type logic
are more sensitive to perturbations in the parameters associated with the
promoter state dynamics than -AND- type. Further analysis shows that the period
of -AND- type coupled dual-feedback oscillators can be tuned without conceding
on the amplitudes. Using these results we derive the basic design principles
governing the robust and tunable synthetic gene oscillators without
compromising on their amplitudes.Comment: 37 pages, 13 figures, 2 table
Enhanced entrainability of genetic oscillators by period mismatch
Biological oscillators coordinate individual cellular components so that they
function coherently and collectively. They are typically composed of multiple
feedback loops, and period mismatch is unavoidable in biological
implementations. We investigated the advantageous effect of this period
mismatch in terms of a synchronization response to external stimuli.
Specifically, we considered two fundamental models of genetic circuits: smooth-
and relaxation oscillators. Using phase reduction and Floquet multipliers, we
numerically analyzed their entrainability under different coupling strengths
and period ratios. We found that a period mismatch induces better entrainment
in both types of oscillator; the enhancement occurs in the vicinity of the
bifurcation on their limit cycles. In the smooth oscillator, the optimal period
ratio for the enhancement coincides with the experimentally observed ratio,
which suggests biological exploitation of the period mismatch. Although the
origin of multiple feedback loops is often explained as a passive mechanism to
ensure robustness against perturbation, we study the active benefits of the
period mismatch, which include increasing the efficiency of the genetic
oscillators. Our findings show a qualitatively different perspective for both
the inherent advantages of multiple loops and their essentiality.Comment: 28 pages, 13 figure
Robustness of circadian clocks to daylight fluctuations: hints from the picoeucaryote Ostreococcus tauri
The development of systemic approaches in biology has put emphasis on
identifying genetic modules whose behavior can be modeled accurately so as to
gain insight into their structure and function. However most gene circuits in a
cell are under control of external signals and thus quantitative agreement
between experimental data and a mathematical model is difficult. Circadian
biology has been one notable exception: quantitative models of the internal
clock that orchestrates biological processes over the 24-hour diurnal cycle
have been constructed for a few organisms, from cyanobacteria to plants and
mammals. In most cases, a complex architecture with interlocked feedback loops
has been evidenced. Here we present first modeling results for the circadian
clock of the green unicellular alga Ostreococcus tauri. Two plant-like clock
genes have been shown to play a central role in Ostreococcus clock. We find
that their expression time profiles can be accurately reproduced by a minimal
model of a two-gene transcriptional feedback loop. Remarkably, best adjustment
of data recorded under light/dark alternation is obtained when assuming that
the oscillator is not coupled to the diurnal cycle. This suggests that coupling
to light is confined to specific time intervals and has no dynamical effect
when the oscillator is entrained by the diurnal cycle. This intringuing
property may reflect a strategy to minimize the impact of fluctuations in
daylight intensity on the core circadian oscillator, a type of perturbation
that has been rarely considered when assessing the robustness of circadian
clocks
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