Systems biology is the iterative and integrative study of biological systems as systems in response to perturbations. It is founded on hypotheses formalized in models built from the results of global functional genomics analyses of the complexity of the genome, transcriptome, proteome, metabolome, etc. Its implementation by cross-disciplinary teams in a standardized mode under quality assurance should allow accessing the small variations of the large number of elements determining functioning of biological systems. Galactose utilization in yeast, and sea urchin development are two examples of emerging systems biology.
Living systems have paradoxical thermodynamic stability, the intrinsic property of self-organization, fluctuation and adaptation to their changing environment. Knowledge accumulated in the analytical reductionist framework has provided useful systematic descriptions of biological systems which appear to be insufficient to gain deep understanding of their behaviour in physiologic conditions and diseases. A state-of-the-art functional genomics study in yeast points to the current inability to appraise 'biological noise', leading to focus on few genes, transcripts and proteins subject to major detectable changes, while currently inaccessible small fluctuations may be major determinants of the behaviour of biological systems. We conjecture that biological systems self-organize because they operate as a conjunction between the relatively variable part of a stable organization and the relatively stable part of a chaotic network of fluctuations, and in a space with a changing number of dimensions: biological space-time. We propose to complement the precepts of the analytical reductionist framework with those of the biosystemic paradigm, in order to explore these conjectures for systems biology, combining in an iterative mode systemic modelling of biological systems, to generate hypotheses, with a high level of standardization of high-throughput experimental platforms, enabling detection of small changes of low-intensity signals, to test them.
We have modeled local DNA sequence parameters to search for DNA architectural motifs involved in transcription regulation and promotion within the Xenopus laevis ribosomal gene promoter and the intergenic spacer (IGS) sequences. The IGS was found to be shaped into distinct topological domains. First, intrinsic bends split the IGS into domains of common but different helical features. Local parameters at inter-domain junctions exhibit a high variability with respect to intrinsic curvature, bendability and thermal stability. Secondly, the repeated sequence blocks of the IGS exhibit righthanded supercoiled structures which could be related to their enhancer properties. Thirdly, the gene promoter presents both inherent curvature and minor groove narrowing which may be viewed as motifs of a structural code for protein recognition and binding. Such pre-existing deformations could simply be remodeled during the binding of the transcription complex. Alternatively, these deformations could pre-shape the promoter in such a way that further remodeling is facilitated. Mutations shown to abolish promoter curvature as well as intrinsic minor groove narrowing, in a variant which maintained full transcriptional activity, bring circumstantial evidence for structurally-preorganized motifs in relation to transcription regulation and promotion. Using well documented X.laevis rDNA regulatory sequences we showed that computer modeling may be of invaluable assistance in assessing encrypted architectural motifs. The evidence of these DNA topological motifs with respect to the concept of structural code is discussed.
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