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1.  Network reconstruction reveals new links between aging and calorie restriction in yeast 
HFSP Journal  2010;4(3-4):94-99.
Aging affects all known organisms and has been studied extensively. Yet, the underlying mechanisms are insufficiently understood, possibly due to the multiscale complexity involved in this process: the aging of multicellular organisms depends on the aging of their cells, which depends on molecular events occurring in each cell. However, the aging of unicellular populations seeded in new niches and the aging of metazoans are surprisingly similar, indicating that the multiscale aspects of aging may have been conserved since the beginnings of cellular life on Earth. This underlines the importance of aging research in unicellular organisms such as a recent study by Lorenz et al., [(2009) Proc. Natl. Acad. Sci. U.S.A. 106, 1145–1150]. In their paper, the authors combine computational network identification with extensive experimentation and literature mining to discover and validate numerous regulatory interactions among ten genes involved in the cellular response to glucose starvation. Since low levels of glucose (calorie restriction) have been known to extend the longevity of various eukaryotes, the authors test the effect of Snf1 kinase overexpression on chronological aging and discover that this key regulator of glucose repression and two of its newly discovered synergistic repressors significantly affect the chronological lifespan of baker’s yeast.
PMCID: PMC2929626  PMID: 21119761
2.  Molecular motors as an auto-oscillator 
HFSP Journal  2010;4(3-4):100-104.
The organization of biomotile systems possesses structural and functional hierarchy, building up from single molecules via protein assemblies and cells further up to an organ. A typical example is the hierarchy of cardiac muscle, on the top of which is the heart. The heartbeat is supported by the rhythmic contraction of the muscle cells that is controlled by the Ca2+ oscillation triggered by periodic electrical excitation of pacemaker cells. Thus, it is usually believed that the heartbeat is governed by the control system based on a sequential one-way chain with the electrical∕chemical information transfer from the upper to the lower level of hierarchy. On the other hand, it has been known for many years that the contractile system of muscle, i.e., skinned muscle fibers and myofibrils, itself possesses the auto-oscillatory properties even in the constant chemical environment. A recent paper [Plaçais, et al. (2009), Phys. Rev. Lett. 103, 158102] demonstrated the auto-oscillatory movement∕tension development in an in vitro motility assay composed of a single actin filament and randomly distributed myosin II molecules, suggesting that the auto-oscillatory properties are inherent to the contractile proteins. Here we discuss how the molecular motors may acquire the higher-ordered auto-oscillatory properties while stepping up the staircase of hierarchy.
PMCID: PMC2929627  PMID: 21119762
3.  Robustness versus evolvability: a paradigm revisited 
HFSP Journal  2010;4(3-4):105-108.
Evolvability is the property of a biological system to quickly adapt to new requirements. Robustness seems to be the opposite. Nonetheless many biological systems display both properties—a puzzling observation, which has caused many debates over the last decades. A recently published model by Draghi et al. [Nature 463, 353–355 (2010)] elegantly circumvents complications of earlier in silico studies of molecular systems and provides an analytical solution, which is surprisingly independent from parameter choice. Depending on the mutation rate and the number of accessible phenotypes at any given genotype, evolvability and robustness can be reconciled. Further research will need to investigate if these parameter settings adequately represent the range of degrees of freedom covered by natural systems and if natural systems indeed assume a state in which both properties, robustness and evolvability, are featured.
PMCID: PMC2929628  PMID: 21119763
4.  Biocrystallography: past, present, future 
HFSP Journal  2010;4(3-4):109-121.
The evolution of biocrystallography from the pioneers’ time to the present era of global biology is presented in relation to the development of methodological and instrumental advances for molecular sample preparation and structure elucidation over the last 6 decades. The interdisciplinarity of the field that generated cross-fertilization between physics- and biology-focused themes is emphasized. In particular, strategies to circumvent the main bottlenecks of biocrystallography are discussed. They concern (i) the way macromolecular targets are selected, designed, and characterized, (ii) crystallogenesis and how to deal with physical and biological parameters that impact crystallization for growing and optimizing crystals, and (iii) the methods for crystal analysis and 3D structure determination. Milestones that have marked the history of biocrystallography illustrate the discussion. Finally, the future of the field is envisaged. Wide gaps of the structural space need to be filed and membrane proteins as well as intrinsically unstructured proteins still constitute challenging targets. Solving supramolecular assemblies of increasing complexity, developing a “4D biology” for decrypting the kinematic changes in macromolecular structures in action, integrating these structural data in the whole cell organization, and deciphering biomedical implications will represent the new frontiers.
PMCID: PMC2929629  PMID: 21119764
5.  Cytoskeletal dynamics in fission yeast: a review of models for polarization and division 
HFSP Journal  2010;4(3-4):122-130.
We review modeling studies concerning cytoskeletal activity of fission yeast. Recent models vary in length and time scales, describing a range of phenomena from cellular morphogenesis to polymer assembly. The components of cytoskeleton act in concert to mediate cell-scale events and interactions such as polarization. The mathematical models reduce these events and interactions to their essential ingredients, describing the cytoskeleton by its bulk properties. On a smaller scale, models describe cytoskeletal subcomponents and how bulk properties emerge.
PMCID: PMC2929630  PMID: 21119765
6.  From genes to neural tube defects (NTDs): insights from multiscale computational modeling 
HFSP Journal  2010;4(3-4):142-152.
The morphogenetic movements, and the embryonic phenotypes they ultimately produce, are the consequence of a series of events that involve signaling pathways, cytoskeletal components, and cell- and tissue-level mechanical interactions. In order to better understand how these events work together in the context of amphibian neurulation, an existing multiscale computational model was augmented. Geometric data for this finite element-based mechanical model were obtained from 3D surface reconstructions of live axolotl embryos and serial sections of fixed specimens. Tissue mechanical properties were modeled using cell-based constitutive equations that include internal force generation and cell rearrangement, and equation parameters were adjusted manually to reflect biochemical changes including alterations in Shroom or the planar-cell-polarity pathway. The model indicates that neural tube defects can arise when convergent extension of the neural plate is reduced by as little as 20%, when it is eliminated on one side of the embryo, when neural ridge elevation is disrupted, when tension in the non-neural ectoderm is increased, or when the ectoderm thickness is increased. Where comparable conditions could be induced in Xenopus embryos, good agreement was found, an important step in model validation. The model reveals the neurulating embryo to be a finely tuned biomechanical system.
PMCID: PMC2929632  PMID: 21119766
7.  Effect of network topology on neuronal encoding based on spatiotemporal patterns of spikes 
HFSP Journal  2010;4(3-4):153-163.
Despite significant progress in our understanding of the brain at both microscopic and macroscopic scales, the mechanisms by which low-level neuronal behavior gives rise to high-level mental processes such as memory still remain unknown. In this paper, we assess the plausibility and quantify the performance of polychronization, a newly proposed mechanism of neuronal encoding, which has been suggested to underlie a wide range of cognitive phenomena. We then investigate the effect of network topology on the reliability with which input stimuli can be distinguished based on their encoding in the form of so-called polychronous groups or spatiotemporal patterns of spikes. We find that small-world networks perform an order of magnitude better than random ones, enabling reliable discrimination between inputs even when prompted by increasingly incomplete recall cues. Furthermore, we show that small-world architectures operate at significantly reduced energetic costs and that their memory capacity scales favorably with network size. Finally, we find that small-world topologies introduce biologically realistic constraints on the optimal input stimuli, favoring especially the topographic inputs known to exist in many cortical areas. Our results suggest that mammalian cortical networks, by virtue of being both small-world and topographically organized, seem particularly well-suited to information processing through polychronization. This article addresses the fundamental question of encoding in neuroscience. In particular, evidence is presented in support of an emerging model of neuronal encoding in the neocortex based on spatiotemporal patterns of spikes.
PMCID: PMC2929633  PMID: 21119767
8.  Spatiotemporal organization of Ca2+ dynamics: a modeling-based approach 
HFSP Journal  2010;4(2):43-51.
Calcium is a ubiquitous second messenger that mediates vital physiological responses such as fertilization, secretion, gene expression, or apoptosis. Given this variety of processes mediated by Ca2+, these signals are highly organized both in time and space to ensure reliability and specificity. This review deals with the spatiotemporal organization of the Ca2+ signaling pathway in electrically nonexcitable cells in which InsP3 receptors are by far the most important Ca2+ channels. We focus on the aspects of this highly regulated dynamical system for which an interplay between experiments and modeling is particularly fruitful. In particular, the importance of the relative densities of the different InsP3 receptor subtypes will be discussed on the basis of a modeling approach linking the steady-state behaviors of these channels in electrophysiological experiments with their behavior in a cellular environment. Also, the interplay between InsP3 metabolism and Ca2+ oscillations will be considered. Finally, we discuss the relationships between stochastic openings of the Ca2+ releasing channels at the microscopic level and the coordinated, regular behavior observed at the whole cell level on the basis of a combined experimental and modeling approach.
PMCID: PMC2931296  PMID: 20885772
9.  Pancreatic islet cells: a model for calcium-dependent peptide release 
HFSP Journal  2010;4(2):52-60.
In mammals the concentration of blood glucose is kept close to 5 mmol∕l. Different cell types in the islet of Langerhans participate in the control of glucose homeostasis. β-cells, the most frequent type in pancreatic islets, are responsible for the synthesis, storage, and release of insulin. Insulin, released with increases in blood glucose promotes glucose uptake into the cells. In response to glucose changes, pancreatic α-, β-, and δ-cells regulate their electrical activity and Ca2+ signals to release glucagon, insulin, and somatostatin, respectively. While all these signaling steps are stimulated in hypoglycemic conditions in α-cells, the activation of these events require higher glucose concentrations in β and also in δ-cells. The stimulus-secretion coupling process and intracellular Ca2+ ([Ca2+]i) dynamics that allow β-cells to secrete is well-accepted. Conversely, the mechanisms that regulate α- and δ-cell secretion are still under study. Here, we will consider the glucose-induced signaling mechanisms in each cell type and the mathematical models that explain Ca2+ dynamics.
PMCID: PMC2931297  PMID: 20885773
10.  A mathematical model of β-cells in an islet of Langerhans sensing a glucose gradient 
HFSP Journal  2010;4(2):61-71.
Pancreatic β-cells release insulin in response to increased glucose levels. Compared to isolated β-cells, β-cells embedded within the islets of Langerhans network exhibit a coordinated and greater insulin secretion response to glucose. This coordinated activity is considered to rely on gap-junctions. We investigated the β-cell electrophysiology and the calcium dynamics in islets in response to glucose gradients. While at constant glucose the network of β-cells fires in a correlated fashion, a glucose gradient induces a sharp division into an active and an inactive part. We hypothesized that this sharp transition is mediated by the specific properties of the gap-junctions. We used a mathematical model of the β-cell electrophysiology in islets to discuss possible origins of this sharp transition in electrical activity. In silico, gap-junctions were required for such a transition. However, the small width of transition was only found when a stochastic variability of the expression of key transmembrane proteins, such as the ATP-dependent potassium channel, was included. The agreement with experimental data was further improved by assuming a delay of gap-junction currents, which points to a role of spatial constraints in the β-cell. This result clearly demonstrates the power of mathematical modeling in disentangling causal relationships in complex systems.
PMCID: PMC2931298  PMID: 20885774
11.  The organization of the secretory machinery in chromaffin cells as a major factor in modeling exocytosis 
HFSP Journal  2010;4(2):85-92.
The organization of cytoplasm in excitable cells was a largely ignored factor when mathematical models were developed to understand intracellular calcium and secretory behavior. Here we employed a combination of fluorescent evanescent and transmitted light microscopy to explore the F-actin cytoskeletal organization in the vicinity of secretory sites in cultured bovine chromaffin cells. This technique and confocal fluorescent microscopy show chromaffin granules associated with the borders of cortical cytoskeletal cages forming an intricate tridimensional network. Furthermore, the overexpression of SNAP-25 in these cells also reveals the association of secretory machinery clusters with the borders of these cytoskeletal cages. The importance of these F-actin cage borders is stressed when granules appear to interact and remain associated during exocytosis visualized in acridin orange loaded vesicles. These results will prompt us to propose a model of cytoskeletal cages, where the secretory machinery is associated with its borders. Both the calcium level and the secretory response are enhanced in this geometrical arrangement when compared with a random distribution of the secretory machinery that is not restricted to the borders of the cage.
PMCID: PMC2931300  PMID: 20885775
12.  Toward reconstructing spike trains from large-scale calcium imaging data 
HFSP Journal  2010;4(1):1-5.
Neural activity can be captured by state-of-the-art optical imaging methods although the analysis of the resulting data sets is often manual and not standardized. Therefore, laboratories using large-scale calcium imaging eagerly await software toolboxes that can automate the process of identifying cells and inferring spikes. An algorithm proposed and implemented in a recent paper by Mukamel et al. [Neuron 63, 747–760 (2009)] used independent component analysis and offers significant improvements over conventional methods. The approach should be widely applicable, as tested with data obtained from the mouse cerebellum, neocortex, and spinal cord. The emergence of analysis tools in parallel with the rapid advances in optical imaging is an exciting development that will stimulate new discoveries and further elucidate the functions of neural circuits.
PMCID: PMC2880024  PMID: 20676302
13.  Systems genetics: the added value of gene expression 
HFSP Journal  2010;4(1):6-10.
Understanding causal relationships between genotypes and phenotypes is a long-standing aim in genetics. In addition to high-throughput technologies that allow the measurement of many DNA variants it is possible to measure gene expression in specific tissues using array technology. “Systems genetics” is an emerging discipline that combines dense data on genotypes, gene expression, and outcome phenotypes to answer fundamental questions about causal pathways from genotype to phenotype. A recent paper by Chen et al. [Mol. Syst. Biol. 5, 310 (2009)] addressed the question of whether relative levels of mRNA expression help to elucidate causal paths from genotype to phenotype, using drug resistance in yeast as a model. The authors show that data on genetic markers and on gene expression, measured in a drug-free environment, can be combined to predict the growth of a yeast strain in the presence of a drug. They argue that their prediction can be used to identify causal pathways and for a subset of the genes used in prediction, the authors demonstrate that these genes cause an effect on drug sensitivity by deleting the gene or overexpressing it or swapping alleles between strains of yeast. This approach can also be applied to other species, including humans, and may become a tool in the study of personalized medicine.
PMCID: PMC2880025  PMID: 20676303
14.  Multiphase flow models of biogels from crawling cells to bacterial biofilms 
HFSP Journal  2010;4(1):11-25.
This article reviews multiphase descriptions of the fluid mechanics of cytoplasm in crawling cells and growing bacterial biofilms. These two systems involve gels, which are mixtures composed of a polymer network permeated by water. The fluid mechanics of these systems is essential to their biological function and structure. Their mathematical descriptions must account for the mechanics of the polymer, the water, and the interaction between these two phases. This review focuses on multiphase flow models because this framework is natural for including the relative motion between the phases, the exchange of material between phases, and the additional stresses within the network that arise from nonspecific chemical interactions and the action of molecular motors. These models have been successful in accounting for how different forces are generated and transmitted to achieve cell motion and biofilm growth and they have demonstrated how emergent structures develop though the interactions of the two phases. A short description of multiphase flow models of tumor growth is included to highlight the flexibility of the model in describing diverse biological applications.
PMCID: PMC2880026  PMID: 20676304
15.  How protein materials balance strength, robustness, and adaptability 
HFSP Journal  2010;4(1):26-40.
Proteins form the basis of a wide range of biological materials such as hair, skin, bone, spider silk, or cells, which play an important role in providing key functions to biological systems. The focus of this article is to discuss how protein materials are capable of balancing multiple, seemingly incompatible properties such as strength, robustness, and adaptability. To illustrate this, we review bottom-up materiomics studies focused on the mechanical behavior of protein materials at multiple scales, from nano to macro. We focus on alpha-helix based intermediate filament proteins as a model system to explain why the utilization of hierarchical structural features is vital to their ability to combine strength, robustness, and adaptability. Experimental studies demonstrating the activation of angiogenesis, the growth of new blood vessels, are presented as an example of how adaptability of structure in biological tissue is achieved through changes in gene expression that result in an altered material structure. We analyze the concepts in light of the universality and diversity of the structural makeup of protein materials and discuss the findings in the context of potential fundamental evolutionary principles that control their nanoscale structure. We conclude with a discussion of multiscale science in biology and de novo materials design.
PMCID: PMC2880027  PMID: 20676305
16.  Relax? Don’t do it!—Linking presynaptic vesicle clustering with mechanical tension 
HFSP Journal  2009;3(6):367-372.
The release of transmitter-filled vesicles from presynaptic terminals is a key step of neurotransmission. Prior to release, synaptic vesicles get clustered at a specialized patch of the presynaptic membrane, here referred to as the active zone. So far, mainly biochemical regulations at the active zone were regarded as decisive for synaptic vesicle clustering and release. However, using biophysical approaches, a recent paper [Siechen, et al. (2009). Proc. Natl. Acad. Sci. U.S.A. 106, 12611–12616] indicated also that the micromechanical regulations within axon and terminal could be crucial for proper vesicle clustering. The authors demonstrated that the synaptic vesicle accumulations vanished after axotomy but were restored after the application of physical tension. Furthermore, axons seem to be under an intrinsic tension, which could be perceived and tuned by an axon-internal tension sensing mechanism. Therefore, mechanical force could steer vesicle clustering and consequently synapse function. Here, we review this interdisciplinary study of Siechen, et al. [Proc. Natl. Acad. Sci. U.S.A. 106, 12611–12616 (2009)] and discuss the significance of cellular mechanics on synaptic function.
PMCID: PMC2839808  PMID: 20514128
17.  How are nucleosomes disrupted during transcription elongation? 
HFSP Journal  2009;3(6):373-378.
Chromatin structure is a powerful tool to regulate eukaryotic transcription. Moreover, nucleosomes are constantly remodeled, disassembled, and reassembled in the body of transcribed genes. Here we propose a general model that explains, in quantitative terms, how transcription elongation affects nucleosome structure at a distance as a result of the positive torque the polymerases create as they translocate along DNA templates.
PMCID: PMC2839809  PMID: 20514129
18.  Stochastic variation: from single cells to superorganisms 
HFSP Journal  2009;3(6):379-385.
Observed phenotype often fails to correspond with genotype. Although it is well established that uncontrolled genetic modifier effects and environmental variability can affect phenotype, stochastic variation in gene expression can also contribute to phenotypic differences. Here we examine recent work that has provided insights into how fundamental physical properties of living cells, and the probabilistic nature of the chemical reactions that underlie gene expression, introduce noise. We focus on instances in which a stochastic decision initiates an event in the development of a multicellular organism and how that decision can be subsequently fixed. We present an example indicating that a similar interplay between an initial stochastic decision and subsequent fixation may underlie the regulation of reproduction in social insects. We argue, therefore, that stochasticity affects biological processes from the single-gene scale through to the complex organization of an ant colony, and represents a largely neglected component of phenotypic variation and evolution.
PMCID: PMC2839810  PMID: 20514130
19.  Early T-cell activation biophysics 
HFSP Journal  2009;3(6):401-411.
The T-cell is one of the main players in the mammalian immune response. It ensures antigen recognition at the surface of antigen-presenting cells in a complex and highly sensitive and specific process, in which the encounter of the T-cell receptor with the agonist peptide associated with the major histocompatibility complex triggers T-cell activation. While signaling pathways have been elucidated in increasing detail, the mechanism of TCR triggering remains highly controversial despite active research published in the past 10 years. In this paper, we present a short overview of pending questions on critical initial events associated with T-cell triggering. In particular, we examine biophysical approaches already in use, as well as future directions. We suggest that the most recent advances in fluorescence super-resolution imaging, coupled with the new classes of genetic fluorescent probes, will play an important role in elucidation of the T-cell triggering mechanism. Beyond this aspect, we predict that exploration of mechanical cues in the triggering process will provide new clues leading to clarification of the entire mechanism.
PMCID: PMC2839812  PMID: 20514131
20.  Propagating waves separate two states of actin organization in living cells 
HFSP Journal  2009;3(6):412-427.
Propagating actin waves are dynamic supramolecular structures formed by the self-assembly of proteins within living cells. They are built from actin filaments together with single-headed myosin, the Arp2∕3 complex, and coronin in a defined three-dimensional order. The function of these waves in structuring the cell cortex is studied on the substrate-attached surface of Dictyostelium cells by the use of total internal reflection fluorescence (TIRF) microscopy. Actin waves separate two areas of the cell cortex from each other, which are distinguished by the arrangement of actin filaments. The Arp2∕3 complex dominates in the area enclosed by a wave, where it has the capacity of building dendritic structures, while the proteins prevailing in the external area, cortexillin I and myosin-II, bundle actin filaments and arrange them in antiparallel direction. Wave propagation is accompanied by transitions in the state of actin with a preferential period of 5 min. Wave generation is preceded by local fluctuations in actin assembly, some of the nuclei of polymerized actin emanating from clathrin-coated structures, others emerging independently. The dynamics of phase transitions has been analyzed to provide a basis for modeling the nonlinear interactions that produce spatio-temporal patterns in the actin system of living cells.
PMCID: PMC2839813  PMID: 20514132
21.  Kicked by Mos and tuned by MPF—the initiation of the MAPK cascade in Xenopus oocytes 
HFSP Journal  2009;3(6):428-440.
The mitogen-activated protein kinase (MAPK) cascade is a paradigmatic signaling cascade, which plays a crucial role in many aspects of cellular events. The main initiator of the cascade in Xenopus oocytes is the oncoprotein Mos. After activation of the cascade, Mos activity is stabilized by MAPK via a feedback loop. Mos concentration levels are, however, not controlled by MAPK alone. In this paper we show, by imposing either a sustained or a peaked activity of M-phase promoting factor (MPF) (Cdc2-cyclin B), how the latter regulates the dynamics of Mos. Our experiments are supported by a detailed kinetic model for the Mos-MPF-MAPK network, which takes into account the three different phosphorylation states of Mos and, as a consequence, allows us to determine the time evolution of Mos under control of MPF. Our work opens a path toward a more complete and biologically realistic quantitative understanding of the dynamic interdependence of Mos and MPF in Xenopus oocytes.
PMCID: PMC2839814  PMID: 20514133
22.  Drosophila morphogenesis: tissue force laws and the modeling of dorsal closure 
HFSP Journal  2009;3(6):441-460.
Dorsal closure, a stage of Drosophila development, is a model system for cell sheet morphogenesis and wound healing. During closure, two flanks of epidermal tissue progressively advance to reduce the area of the eye-shaped opening in the dorsal surface, which contains amnioserosa tissue. To simulate the time evolution of the overall shape of the dorsal opening, we developed a mathematical model, in which contractility and elasticity are manifest in model force-producing elements that satisfy force-velocity relationships similar to muscle. The action of the elements is consistent with the force-producing behavior of actin and myosin in cells. The parameters that characterize the simulated embryos were optimized by reference to experimental observations on wild-type embryos and, to a lesser extent, on embryos whose amnioserosa was removed by laser surgery and on myospheroid mutant embryos. Simulations failed to reproduce the amnioserosa-removal protocol in either the elastic or the contractile limit, indicating that both elastic and contractile dynamics are essential components of the biological force-producing elements. We found it was necessary to actively upregulate forces to recapitulate both the double and single-canthus nick protocols, which did not participate in the optimization of parameters, suggesting the existence of additional key feedback mechanisms.
PMCID: PMC2839815  PMID: 20514134
23.  Frontiers in Life Science 
HFSP Journal  2010;4(3-4):93.
PMCID: PMC2929625  PMID: 20811566
24.  Inherited adaptation of genome-rewired cells in response to a challenging environment 
HFSP Journal  2010;4(3-4):131-141.
Despite their evolutionary significance, little is known about the adaptation dynamics of genomically rewired cells in evolution. We have confronted yeast cells carrying a rewired regulatory circuit with a severe and unforeseen challenge. The essential HIS3 gene from the histidine biosynthesis pathway was placed under the exclusive regulation of the galactose utilization system. Glucose containing medium strongly represses the GAL genes including HIS3 and these rewired cells are required to operate this essential gene. We show here that although there were no adapted cells prior to the encounter with glucose, a large fraction of cells adapted to grow in this medium and this adaptation was stably inherited. The adaptation relied on individual cells that switched into an adapted state and, thus, the adaptation was due to a response of many individual cells to the change in environment and not due to selection of rare advantageous phenotypes. The adaptation of numerous individual cells by heritable phenotypic switching in response to a challenge extends the common evolutionary framework and attests to the adaptive potential of regulatory circuits.
PMCID: PMC2929631  PMID: 20811567
25.  Integrating ELF4 into the circadian system through combined structural and functional studies 
HFSP Journal  2009;3(5):350-366.
The circadian clock is a timekeeping mechanism that enables anticipation of daily environmental changes. In the plant Arabidopsis thaliana, the circadian system is a multiloop series of interlocked transcription-translation feedbacks. Several genes have been arranged in these oscillation loops, but the position of the core-clock gene ELF4 in this network was previously undetermined. ELF4 lacks sequence similarity to known domains, and functional homologs have not yet been identified. Here we show that ELF4 is functionally conserved within a subclade of related sequences, and forms an alpha-helical homodimer with a likely electrostatic interface that could be structurally modeled. We support this hypothesis by expression analysis of new elf4 hypomorphic alleles. These weak mutants were found to have expression level phenotypes of both morning and evening clock genes, implicating multiple entry points of ELF4 within the multiloop network. This could be mathematically modeled. Furthermore, morning-expression defects were particular to some elf4 alleles, suggesting predominant ELF4 action just preceding dawn. We provide a new hypothesis about ELF4 in the oscillator—it acts as a homodimer to integrate two arms of the circadian clock.
PMCID: PMC2801535  PMID: 20357892

Results 1-25 (142)