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Systems biology takes an interdisciplinary approach to the systematic study of complex interactions in biological systems. This approach seeks to decipher the emergent behaviors of complex systems rather than focusing only on their constituent properties. As an increasing number of examples illustrate the value of systems biology approaches to understand the initiation, progression, and treatment of cancer, systems biologists from across Europe and the United States hope for changes in the way their field is currently perceived among cancer researchers. In a recent EU-US workshop, supported by the European Commission, the German Federal Ministry for Education and Research, and the National Cancer Institute of the NIH, the participants discussed the strengths, weaknesses, hurdles, and opportunities in cancer systems biology.

The complexity of tissue- and day time-specific regulation of thousands of clock-controlled genes (CCGs) suggests that many regulatory mechanisms contribute to the transcriptional output of the circadian clock. We aim to predict these mechanisms using a large scale promoter analysis of CCGs. Our study is based on a meta-analysis of DNA-array data from rodent tissues. We searched in the promoter regions of 2065 CCGs for highly overrepresented transcription factor binding sites. In order to compensate the relatively high GC-content of CCG promoters, a novel background model to avoid a bias towards GC-rich motifs was employed. We found that many of the transcription factors with overrepresented binding sites in CCG promoters exhibit themselves circadian rhythms. Among the predicted factors are known regulators such as CLOCK:BMAL1, DBP, HLF, E4BP4, CREB, RORα and the recently described regulators HSF1, STAT3, SP1 and HNF-4α. As additional promising candidates of circadian transcriptional regulators PAX-4, C/EBP, EVI-1, IRF, E2F, AP-1, HIF-1 and NF-Y were identified. Moreover, GC-rich motifs (SP1, EGR, ZF5, AP-2, WT1, NRF-1) and AT-rich motifs (MEF-2, HMGIY, HNF-1, OCT-1) are significantly overrepresented in promoter regions of CCGs. Putative tissue-specific binding sites such as HNF-3 for liver, NKX2.5 for heart or Myogenin for skeletal muscle were found. The regulation of the erythropoietin (Epo) gene was analysed, which exhibits many binding sites for circadian regulators. We provide experimental evidence for its circadian regulated expression in the adult murine kidney. Basing on a comprehensive literature search we integrate our predictions into a regulatory network of core clock and clock-controlled genes. Our large scale analysis of the CCG promoters reveals the complexity and extensiveness of the circadian regulation in mammals. Results of this study point to connections of the circadian clock to other functional systems including metabolism, endocrine regulation and pharmacokinetics.

The circadian clock is a biological system providing an internal self-sustained temporal framework and adaptation mechanisms to the daily environmental rhythm. One of its behavioral implication in humans is the sleep-wake cycle. The core mammalian circadian clock is a system composed of interacting regulatory feedback loops present in many tissues throughout the body. The core set of circadian clock genes codes for proteins feeding back to regulate not only their own expression, but also that of clock output genes and regulatory pathways. Still, however, our understanding of processes regulated in a circadian fashion and the linkage between the molecular system and behavioral or physiological outputs is poor. Our work aims at identification of clock-controlled genes (CCGs) and their regulatory motifs. We analyzed several microarray measurements of genes with a daily oscillating expression and extracted 2065 of them together with their peak expression phases and oscillation amplitudes. For an in-depth analysis we selected a subset of 167 genes reported by multiple microarray experiments. Gene promoters were scanned in the search for known regulatory motifs of clock genes (E-Box, RRE, D-Box, CRE) as well as other over-represented regulatory motifs. We found an over-representation of the E-boxes and D-boxes in the selected subset of 167 CCGs. This over-representation is smaller when the list of 2065 genes is analyzed. The search for other regulatory motifs contained in the TRANSFAC database revealed a strong over-representation of some of them such as Spl, AP-2, STAT1, HIF-1 and E2F. The signals found in the promoter sequences indicate possible regulatory mechanisms important for the coordination of circadian rhythms.

Protein interactions constitute the backbone of the cellular machinery in living systems. Their biological importance has led to systematic assemblies of large-scale protein-protein interaction maps for various organisms. Recently, the focus of such interactome projects has shifted towards the elucidation of the human interaction network. Several strategies have been employed to gain comprehensive maps of protein interactions occurring in the human body. For their efficient analysis, graph theory has become a favourite tool. It can identify characteristic features of interaction networks which can give us important insights into the general structure of the underlying molecular networks. Although such graph-theoretical analyses have delivered us a variety of interesting results, their general validity remains to be demonstrated. We therefore examined whether independently assembled human interaction networks show common structural features. Remarkably, while some general graph-theoretical features were found, we detected a strong dependency of network structures on the method used to generate the network. Our study strongly indicates that graph-theoretical analysis can be severely compromised by the observed structural divergence and reassessment of earlier results might be warranted.

We analyze two symmetric two-mass models of the avian syrinx. Our first model applies to songbirds and is a rescaled version of the well-known human two-mass model. Our second model (trapezoidal model) introduces a smoother geometry and is used to simulate the ring dove (Streptopelia risoria) syrinx. Simulations show that both models exhibit self-sustained vibrations. We show that the occurrence of collisions and the intensity of harmonics depend strongly on the configuration of the syrinx. The songbird model does not present instabilities. The trapezoidal model, however, displays coexisting limit-cycles that represent vibrations with, and without collisions at the same pressure. Register-like transitions are accompanied by subharmonics and deterministic chaos.

International audience; Huntington's Disease (HD) is a late-onset, progressively degenerative brain disorder characterized by cell loss in the striatum and cortex. HD is caused by a polyglutamine (polyQ) expansion in the protein huntingtin (Htt). The mutant Htt is a substrate for caspases -2, -3 and -6. The cleavage of mutant Htt by caspase-2 has been suggested to underlie the selective neuronal death in HD. Once the mutant Htt is cleaved, a sticky and toxic fragment with the potential to form aggregates is released. The role of aggregation in the progression of HD has been extensively studied, yielding a plethora of ambivalent results. It has been shown that these are the diffuse, monomeric and oligomeric, forms of the mutant Htt fragment rather than the aggregates that are the major source of toxicity to the cells. We present here a mathematical model for aggregation in HD and discuss how it can relate to the selective neuronal death and the dependence of the disease onset on polyQ length. We describe the dynamical behavior of caspase-2, the release of monomeric forms of the mutant Htt fragment and the aggregation of these fragments through intermediate steps. Our model predicts that the concentration of toxic, intermediate oligomeric structures does not increase with increased caspase activity. We therefore suggest that the intermediate oligomeric forms of toxic Htt fragment do not account for selective and polyQ dependent neuronal death.

Contains fulltext : 47556.pdf ( ) (Open Access) BACKGROUND: Whole genome sequencing of marine cyanobacteria has revealed an unprecedented degree of genomic variation and streamlining. With a size of 1.66 megabase-pairs, Prochlorococcus sp. MED4 has the most compact of these genomes and it is enigmatic how the few identified regulatory proteins efficiently sustain the lifestyle of an ecologically successful marine microorganism. Small non-coding RNAs (ncRNAs) control a plethora of processes in eukaryotes as well as in bacteria; however, systematic searches for ncRNAs are still lacking for most eubacterial phyla outside the enterobacteria. RESULTS: Based on a computational prediction we show the presence of several ncRNAs (cyanobacterial functional RNA or Yfr) in several different cyanobacteria of the Prochlorococcus-Synechococcus lineage. Some ncRNA genes are present only in two or three of the four strains investigated, whereas the RNAs Yfr2 through Yfr5 are structurally highly related and are encoded by a rapidly evolving gene family as their genes exist in different copy numbers and at different sites in the four investigated genomes. One ncRNA, Yfr7, is present in at least seven other cyanobacteria. In addition, control elements for several ribosomal operons were predicted as well as riboswitches for thiamine pyrophosphate and cobalamin. CONCLUSION: This is the first genome-wide and systematic screen for ncRNAs in cyanobacteria. Several ncRNAs were both computationally predicted and their presence was biochemically verified. These RNAs may have regulatory functions and each shows a distinct phylogenetic distribution. Our approach can be applied to any group of microorganisms for which more than one total genome sequence is available for comparative analysis.