Regulatory motifs in bacteria can be found by local multiple alignment of upstream regions from coregulated sets of genes, or regulons. Previously, genes with similar mRNA expression patterns have been used to predict regulons. We compare the use of three additional potentially coregulated collections of genes: genes that make up functional pathways, genes homologous to regulons from a well-studied species (Escherichia coli), and groups of genes derived from conserved operons. In different species, genes making up homologous regulons are often assorted into coregulated operons in different combinations. This allows partial reconstruction of regulons by looking at operon structure across several species. Unlike the use of mRNA expression data, this method of predicting coregulated sets of genes does not depend on the growth conditions used.
We used these groups of genes to search for regulatory motifs in 17 complete microbial genomes using the program AlignACE. New, statistically significant motifs were found using each grouping method and in each organism. The most significant new motif was found upstream of genes in the methane metabolism functional group in Methanobacterium thermoautotrophicum. We found that at least 27% of the known Escherichia coli DNA regulatory motifs are conserved in distantly related eubacteria. We also observed different but significant motifs in other organisms upstream of genes homologous to members of known E. coli regulons, including Crp, LexA, and ArcA in Bacillus subtilis; four anaerobic regulons in Archaeoglobus fulgidus (NarL, NarP, Fnr, and ModE); and PhoB, PurR, RpoH, and FhlA in other archaebacterial species. In addition, we use motif conservation to aid in finding new motifs by grouping upstream regions from closely related bacteria, thus increasing the number of instances of the motif in the sequence to be aligned. By grouping upstream sequences from three archaebacterial species, we found a conserved motif that may regulate ferrous ion transport. Motif discovery by the strategies described here will become increasingly powerful as the amount of available genome sequence increases.
McGuire, A. M., Hughes, J. D., and Church, G. M. Conservation of DNA regulatory motifs and d iscovery of new motifs in microbial genomes. Genome Research. 10: 744-757, 2000.
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