Functional genomics in higher eukaryotes faces major challenges attributable to the ever-increasing complexity of the regulatory circuitry and its biological manifestation. The genomic regulon remains largely inaccessible to bioinformatics tools due to a degree of apparent functional redundancy (degeneration) of the underlying code and nonlinearities of its cellular interpretation. Based on recent biochemical work on transcription coregulators and their crosstalk with other genome maintenance and regulation pathways, a model is developed that offers an explanation how the cellular transcription machinery interprets the gene regulatory code. The experimental evidence suggests a secondary layer of coding by the chromatin structure of the genome producing hypercycles of repressed and open nucleosomal sites in euchromatin. The code is read out by coregulators analog and prior to the reading out of the primary coding (the nucleotide sequence) by transcriptionfactors. The coregulator model of transcription thus promises not only to enhance our comprehension of the biological phenomena leading to faithful gene regulation in higher eukaryotes, but also to overcome some of the above-described impediments to bioinformatic analysis, and it may lead to the systematic description of gene regulatory networks and their dynamics. The implications of a coregulator-based view of transcription for the development of tools analyzing genomes of higher eukaryotes for complex, composite nucleotide patterns derived from above molecular understanding are significant. Furthermore, the recent generation of systematic gene expression information in response to specific cellular signals can be utilized, within limits, as training data in multiple-round feed-back optimization of these complex search expressions.

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