Center for Systems Biology at Edinburgh

King's Lynn, United Kingdom

Center for Systems Biology at Edinburgh

King's Lynn, United Kingdom
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Kopp-Scheinpflug C.,University of Leicester | Tozer A.,University of Leicester | Robinson S.,University of Leicester | Tempel B.,University of Washington | And 3 more authors.
Neuron | Year: 2011

Offset responses upon termination of a stimulus are crucial for perceptual grouping and gap detection. These gaps are key features of vocal communication, but an ionic mechanism capable of generating fast offsets from auditory stimuli has proven elusive. Offset firing arises in the brainstem superior paraolivary nucleus (SPN), which receives powerful inhibition during sound and converts this into precise action potential (AP) firing upon sound termination. Whole-cell patch recording in vitro showed that offset firing was triggered by IPSPs rather than EPSPs. We show that AP firing can emerge from inhibition through integration of large IPSPs, driven by an extremely negative chloride reversal potential (ECl), combined with a large hyperpolarization-activated nonspecific cationic current (IH), with a secondary contribution from a T-type calcium conductance (ITCa). On activation by the IPSP, IH potently accelerates the membrane time constant, so when the sound ceases, a rapid repolarization triggers multiple offset APs that match onset timing accuracy. © 2011 Elsevier Inc.

Blanc M.,University of Edinburgh | Hsieh W.Y.,University of Edinburgh | Robertson K.A.,University of Edinburgh | Robertson K.A.,Center for Systems Biology at Edinburgh | And 20 more authors.
PLoS Biology | Year: 2011

Little is known about the protective role of inflammatory processes in modulating lipid metabolism in infection. Here we report an intimate link between the innate immune response to infection and regulation of the sterol metabolic network characterized by down-regulation of sterol biosynthesis by an interferon regulatory loop mechanism. In time-series experiments profiling genome-wide lipid-associated gene expression of macrophages, we show a selective and coordinated negative regulation of the complete sterol pathway upon viral infection or cytokine treatment with IFNγ or β but not TNF, IL1β, or IL6. Quantitative analysis at the protein level of selected sterol metabolic enzymes upon infection shows a similar level of suppression. Experimental testing of sterol metabolite levels using lipidomic-based measurements shows a reduction in metabolic output. On the basis of pharmacologic and RNAi inhibition of the sterol pathway we show augmented protection against viral infection, and in combination with metabolite rescue experiments, we identify the requirement of the mevalonate-isoprenoid branch of the sterol metabolic network in the protective response upon statin or IFNβ treatment. Conditioned media experiments from infected cells support an involvement of secreted type 1 interferon(s) to be sufficient for reducing the sterol pathway upon infection. Moreover, we show that infection of primary macrophages containing a genetic knockout of the major type I interferon, IFNβ, leads to only a partial suppression of the sterol pathway, while genetic knockout of the receptor for all type I interferon family members, ifnar1, or associated signaling component, tyk2, completely abolishes the reduction of the sterol biosynthetic activity upon infection. Levels of the proteolytically cleaved nuclear forms of SREBP2, a key transcriptional regulator of sterol biosynthesis, are reduced upon infection and IFNβ treatment at both the protein and de novo transcription level. The reduction in srebf2 gene transcription upon infection and IFN treatment is also found to be strictly dependent on ifnar1. Altogether these results show that type 1 IFN signaling is both necessary and sufficient for reducing the sterol metabolic network activity upon infection, thereby linking the regulation of the sterol pathway with interferon anti-viral defense responses. These findings bring a new link between sterol metabolism and interferon antiviral response and support the idea of using host metabolic modifiers of innate immunity as a potential antiviral strategy. © 2011 Blanc et al.

Pokhilko A.,University of Edinburgh | Hodge S.K.,University of Edinburgh | Stratford K.,University of Edinburgh | Knox K.,University of Edinburgh | And 6 more authors.
Molecular Systems Biology | Year: 2010

Circadian clocks generate 24-h rhythms that are entrained by the day/night cycle. Clock circuits include several light inputs and interlocked feedback loops, with complex dynamics. Multiple biological components can contribute to each part of the circuit in higher organisms. Mechanistic models with morning, evening and central feedback loops have provided a heuristic framework for the clock in plants, but were based on transcriptional control. Here, we model observed, post-transcriptional and post-translational regulation and constrain many parameter values based on experimental data. The model's feedback circuit is revised and now includes PSEUDO-RESPONSE REGULATOR 7 (PRR7) and ZEITLUPE. The revised model matches data in varying environments and mutants, and gains robustness to parameter variation. Our results suggest that the activation of important morning-expressed genes follows their release from a night inhibitor (NI). Experiments inspired by the new model support the predicted NI function and show that the PRR5 gene contributes to the NI. The multiple PRR genes of Arabidopsis uncouple events in the late night from light-driven responses in the day, increasing the flexibility of rhythmic regulation. © 2010 EMBO and Macmillan Publishers Limited.

Wenden B.,University of Edinburgh | Kozma-Bognar L.,University of Edinburgh | Kozma-Bognar L.,Hungarian Academy of Sciences | Edwards K.D.,University of Edinburgh | And 5 more authors.
Plant Journal | Year: 2011

The circadian clock is a fundamental feature of eukaryotic gene regulation that is emerging as an exemplar genetic sub-network for systems biology. The circadian system in Arabidopsis plants is complex, in part due to its phototransduction pathways, which are themselves under circadian control. We therefore analysed two simpler experimental systems. Etiolated seedlings entrained by temperature cycles showed circadian rhythms in the expression of genes that are important for the clock mechanism, but only a restricted set of downstream target genes were rhythmic in microarray assays. Clock control of phototransduction pathways remained robust across a range of light inputs, despite the arrhythmic transcription of light-signalling genes. Circadian interactions with light signalling were then analysed using a single active photoreceptor. Phytochrome A (phyA) is expected to be the only active photoreceptor that can mediate far-red (FR) light input to the circadian clock. Surprisingly, rhythmic gene expression was profoundly altered under constant FR light, in a phyA-dependent manner, resulting in high expression of evening genes and low expression of morning genes. Dark intervals were required to allow high-amplitude rhythms across the transcriptome. Clock genes involved in this response were identified by mutant analysis, showing that the EARLY FLOWERING 4 gene is a likely target and mediator of the FR effects. Both experimental systems illustrate how profoundly the light input pathways affect the plant circadian clock, and provide strong experimental manipulations to understand critical steps in the plant clock mechanism. © 2011 Blackwell Publishing Ltd.

Huang W.,Center for Research in Agricultural Genomics | Perez-Garcia P.,Center for Research in Agricultural Genomics | Pokhilko A.,University of Edinburgh | Millar A.J.,University of Edinburgh | And 5 more authors.
Science | Year: 2012

In many organisms, the circadian clock is composed of functionally coupled morning and evening oscillators. In Arabidopsis, oscillator coupling relies on a core loop in which the evening oscillator component TIMING OF CAB EXPRESSION 1 (TOC1) was proposed to activate a subset of morning-expressed oscillator genes. Here, we show that TOC1 does not function as an activator but rather as a general repressor of oscillator gene expression. Repression occurs through TOC1 rhythmic association to the promoters of the oscillator genes. Hormone-dependent induction of TOC1 and analysis of RNA interference plants show that TOC1 prevents the activation of morning-expressed genes at night. Our study overturns the prevailing model of the Arabidopsis circadian clock, showing that the morning and evening oscillator loops are connected through the repressing activity of TOC1.

Karcz A.,University of Leipzig | Hennig M.H.,University of Edinburgh | Hennig M.H.,Center for Systems Biology at Edinburgh | Robbins C.A.,University of Washington | And 3 more authors.
Journal of Physiology | Year: 2011

Voltage-gated potassium (Kv) channels containing Kv1.1 subunits are strongly expressed in neurons that fire temporally precise action potentials (APs). In the auditory system, AP timing is used to localize sound sources by integrating interaural differences in time (ITD) and intensity (IID) using sound arriving at both cochleae. In mammals, the first nucleus to encode IIDs is the lateral superior olive (LSO), which integrates excitation from the ipsilateral ventral cochlear nucleus and contralateral inhibition mediated via the medial nucleus of the trapezoid body. Previously we reported that neurons in this pathway show reduced firing rates, longer latencies and increased jitter in Kv1.1 knockout (Kcna1-/-) mice. Here, we investigate whether these differences have direct impact on IID processing by LSO neurons. Single-unit recordings were made from LSO neurons of wild-type (Kcna1+/+) and from Kcna1-/- mice. IID functions were measured to evaluate genotype-specific changes in integrating excitatory and inhibitory inputs. In Kcna1+/+ mice, IID sensitivity ranged from +27 dB (excitatory ear more intense) to -20 dB (inhibitory ear more intense), thus covering the physiologically relevant range of IIDs. However, the distribution of IID functions in Kcna1-/- mice was skewed towards positive IIDs, favouring ipsilateral sound positions. Our computational model revealed that the reduced performance of IID encoding in the LSO of Kcna1-/- mice is mainly caused by a decrease in temporal fidelity along the inhibitory pathway. These results imply a fundamental role for Kv1.1 in temporal integration of excitation and inhibition during sound source localization. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.

O'Neill J.S.,University of Cambridge | O'Neill J.S.,Center for Systems Biology at Edinburgh | Van Ooijen G.,Center for Systems Biology at Edinburgh | Le Bihan T.,Center for Systems Biology at Edinburgh | And 2 more authors.
Journal of Biological Rhythms | Year: 2011

To refine mathematical models of the transcriptional/translational feedback loop in the clockwork of Arabidopsis thaliana, the investigators sought to determine the affinity of the transcription factors LHY, CCA1, and CHE for their cognate DNA target sequences in vitro. Steady-state dissociation constants were observed to lie in the low nanomolar range. Furthermore, the data suggest that the LHY/CCA1 heterodimer binds more tightly than either homodimer and that DNA binding of these complexes is temperature compensated. Finally, it was found that LHY binding to the evening element in vitro is enhanced by both molecular crowding effects and by casein kinase 2-mediated phosphorylation. © 2011 SAGE Publications.

Chew Y.H.,University of Edinburgh | Halliday K.J.,University of Edinburgh | Halliday K.J.,Center for Systems Biology at Edinburgh
Current Opinion in Biotechnology | Year: 2011

Global concerns such as food security and climate change have highlighted an urgent need for improved crop yield. Breakthroughs in Arabidopsis research provide fresh application routes to achieve novel crop varieties that can withstand or avoid stresses imposed by a changing growth environment. This review features advances in CBF-stress signalling that expand opportunities to produce super hardy crops that can withstand multiple abiotic stresses. It examines molecular external coincidence mechanisms that avoid abiotic stresses by confining plant growth and reproduction to favourable times of the year. The potential value of mathematical modelling approaches is discussed in relation to improving crop-stress resistance or avoidance, and forecasting crop performance. © 2010.

Pokhilko A.,University of Edinburgh | Ramos J.A.,Mendel Biotechnology | Holtan H.,Mendel Biotechnology | Maszle D.R.,Mendel Biotechnology | And 3 more authors.
Journal of Theoretical Biology | Year: 2011

The E3 ubiquitin ligase COP1 (CONSTITUTIVE PHOTOMORPHOGENIC1) plays a key role in the repression of the plant photomorphogenic development in darkness. In the presence of light, COP1 is inactivated by a mechanism which is not completely understood. This leads to accumulation of COP1's target transcription factors, which initiates photomorphogenesis, resulting in dramatic changes of the seedling's physiology.Here we use a mathematical model to explore the possible mechanism of COP1 modulation upon dark/light transition in Arabidopsis thaliana based upon data for two COP1 target proteins: HY5 and HFR1, which play critical roles in photomorphogenesis. The main reactions in our model are the inactivation of COP1 by a proposed photoreceptor-related inhibitor I and interactions between COP1 and a CUL4 (CULLIN4)-based ligase. For building and verification of the model, we used the available published and our new data on the kinetics of HY5 and HFR1 together with the data on COP1 abundance. HY5 has been shown to accumulate at a slower rate than HFR1. To describe the observed differences in the timecourses of the "slow" target HY5 and the "fast" target HFR1, we hypothesize a switch between the activities of COP1 and CUL4 ligases upon dark/light transition, with COP1 being active mostly in darkness and CUL4 in light. The model predicts a bi-phasic kinetics of COP1 activity upon the exposure of plants to light, with its restoration after the initial decline and the following slow depletion of the total COP1 content. CUL4 activity is predicted to increase in the presence of light. We propose that the ubiquitin ligase switch is important for the complex regulation of multiple transcription factors during plants development. In addition, this provides a new mechanism for sensing the duration of light period, which is important for seasonal changes in plant development. © 2010 Elsevier Ltd.

Watterson S.,University of Edinburgh | Watterson S.,Center for Systems Biology at Edinburgh | Ghazal P.,University of Edinburgh | Ghazal P.,Center for Systems Biology at Edinburgh
Future Microbiology | Year: 2010

Biological pathways link the molecular and cellular levels of biological activity and perform complex information processing seamlessly. Systems biology aims to combine an understanding of the cause-effect relationships of each individual interaction to build an understanding of the function of whole pathways. Therapies that target the 'host biological processes in infectious diseases are often limited to the use of vaccines and biologics rather than small molecules. The development of host drug targets for small molecules is constrained by a limited knowledge of the underlying role of each target, particularly its potential to cause harmful side effects after targeting. By considering the combinatorial complexity of pathways from the outset, we can develop modeling tools that are better suited to analyzing large pathways, enabling us to identify new causal relationships. This could lead to new drug target strategies that beneficially disrupt host-pathogen interactions, minimizing the number of side effects. We introduce logic theory as part of a pathway modeling approach that can provide a new framework for understanding pathways and refine 'host-based drug target identification strategies. © 2010 Steven Watterson.

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