| Bacillus subtilis is the main model system for the study of Gram-positive bacteria and is relied upon for gene function inference for numerous species. However, many B. subtilis genes are of unknown function. An accurate model of the B. subtilis transcriptional regulatory network will help to accelerate the pace of gene function identification and pathway organization in this important model system. Accurate models of regulatory systems need the integration of multiple forms of evidence. Biclustering, the simultaneous grouping of genes and experiments, has been useful for the analysis of multiple systems biology data types. The integrative biclustering algorithm cMonkey groups genes into co-regulated condition-dependent modules based on factors such as co-expression, shared upstream sequence motifs, and known associations. Multi-species cMonkey biclusters data from multiple species to identify conserved co-regulated groups of orthologous genes. Examination of gene modules from multi-species cMonkey biclustering performed on pairings between B. subtilis, B. anthracis, and L. monocytogenes resulted in the discovery of a probable transcriptional rewiring event in the sporulation program of B. anthracis and yielded insight into the loss of motility in B. anthracis. A model of the global transcriptional regulatory network of B. subtilis was constructed using known regulatory interactions and two large transcription datasets. Both cMonkey and multi-species cMonkey were used to group genes into co-regulated condition-dependent modules. Network inference was performed using a new version of the Inferelator designed to use known regulatory interactions to constrain network model selection. Inferelator is an algorithm that identifies potentially causative relationships between transcriptional regulators and genes (or groups of genes). This approach was able to confidently predict 66% of known regulatory interactions in B. subtilis. Exploration of the model shows gene modules devoted to various aspects of B. subtilis biology, including biofilm formation, competence, motility, and sporulation and lead to the discovery of three new sporulation genes in B. subtilis. Further characterization of one of these genes suggests a mechanism for synthesis of the polysaccharide component of the spore envelope. |
