  The genetic regulatory network (GRN) plays a key role in controlling the
response of the cell to changes in the environment. Although the structure of
GRNs has been the subject of many studies, their large scale structure in the
light of feedbacks from the metabolic network (MN) has received relatively
little attention. Here we study the causal structure of the GRNs, namely the
chain of influence of one component on the other, taking into account feedback
from the MN. First we consider the GRNs of E. coli and B. subtilis without
feedback from MN and illustrate their causal structure. Next we augment the
GRNs with feedback from their respective MNs by including (a) links from genes
coding for enzymes to metabolites produced or consumed in reactions catalyzed
by those enzymes and (b) links from metabolites to genes coding for
transcription factors whose transcriptional activity the metabolites alter by
binding to them. We find that the inclusion of feedback from MN into GRN
significantly affects its causal structure, in particular the number of levels
and relative positions of nodes in the hierarchy, and the number and size of
the strongly connected components (SCCs). We then study the functional
significance of the SCCs. For this we identify condition specific feedbacks
from the MN into the GRN by retaining only those enzymes that are essential for
growth in specific environmental conditions simulated via the technique of flux
balance analysis (FBA). We find that the SCCs of the GRN augmented by these
feedbacks can be ascribed specific functional roles in the organism. Our
algorithmic approach thus reveals relatively autonomous subsystems with
specific functionality, or regulatory modules in the organism. This automated
approach could be useful in identifying biologically relevant modules in other
organisms for which network data is available, but whose biology is less well
studied.
