The availability of complete genome sequences and global gene expression profiling
represents a promising strategy for reverse engineering genetic regulatory circuits.
We are describing a novel strategy for analyzing gene expression and genomic
sequence to elucidate the cis-regulatory design in terms of higher order modular
architecture of the transcription control regions. The large-scale transcriptional
activity was assessed in two distinct experimental models represented by reovirus
infection and brain extracts from mice selectively bred for high vs. low alcohol
functional tolerance. A comparison of the 2000 nucleotides of the upstream sequences
of the most differentially expressed genes revealed regions of significant
similarity which displayed a highly conserved modular organization. Higher-order
patterns of individual modules were also over-represented in the 5' upstream regions
of the analyzed genes. The supermodules contain binding sites for multiple
transcription factors and they tend to define the role of genes in processes
involved in either viral infection or mechanisms responsible for different levels of
alcohol functional tolerance. The supermodular design unravels a different aspect of
the circuitry encoding cis-regulatory logic responsible for transducing the upstream
signaling to control the expression of genes in similar biological processes.