Multiple parallel feed-forward loops regulate the use of different carbon sources
Cellular feeding, which includes the uptake of carbon and energy sources and their metabolism, can be considered as one of the main physiological processes in bacterial systems. The regulation of these processes directly affects cellular fitness. The selection of carbon sources is regulated by CRP and about 20 more specific TFs (Fig. 2a). The hierarchical organisation of the corresponding subnetwork is characterized by a short average path length (cf. Table 1). Regulatory interactions between CRP and the specific TFs result in the occurrence of multiple feed-forward loops (FFLs) for the use of alternative sugar sources. FFL is a network motif recurrently found in transcriptional networks and is defined as a three-gene pattern composed of two input TFs, one of which regulates the other, both jointly regulating a target gene.9,24 Based on the mode of regulation of each TF, this motif is subdivided into eight different subtypes.24 Coherent FFL type 1 corresponds to all the regulatory interactions in the motif being positive; in incoherent type 1 FFL, the first TF regulates positively both the targets, although the second TF represses the expression of the target gene thereby reversing the final effect. The majority of the FFLs present in the subnetwork for carbon catabolism belong to coherent and incoherent type 1 groups,24 with both TFs working together, as a result of a persistent signal affecting the global TF (in this case, cAMP) and the presence of a signal affecting a TF corresponding to a sugar alternative to glucose.24–26 This motif structure enables the filtering of short pulses of the signal affecting the global TF (cAMP) in case of transient glucose deprivation. Consequently, the target structural genes are activated only in the persistent absence of glucose and in the presence of an alternative carbon source.
The phosphotransferase system typically transports and phosphorylates certain sugars, including glucose, a preferred carbon source for E. coli, and this condition ultimately results in low levels of cAMP. Consequently, CRP does not activate the transcription of the genes responsible for the degradation of alternative sugars. Note that most structural genes involved in the transport and initial catabolism of alternative carbon sources are encoded in operons, each specifically repressed in the absence of the inducing sugar.
When glucose is lacking, cAMP level increases and CRP can activate the transcription of genes responsible for degrading alternative carbon sources.27 Simultaneously, sugars (or a processed variant thereof) present in the cell bind their specific TF; allosteric interactions then result in TF unbinding from DNA, alleviating the repression and permitting the transcription of the corresponding target genes. This organisation involving multiple parallel FFLs coupled to phosphotransferase activity appears optimal for enabling rapid transcriptional responses to sudden lack of glucose in the presence of alternative carbon sources in the milieu.28,29