Extrinsic noise of the target gene governs abundance pattern of feed-forward loop motifs

Feed-forward loop (FFL) is found to be a recurrent structure in bacterial and yeast gene transcription regulatory networks. In a generic FFL, transcription factor (TF) S regulates production of another TF X while both of these TFs regulate production of final gene-product Y. Depending upon the regulatory programs (activation or repression), FFLs are grouped into two broad classes: coherent (C) and incoherent (I), each class containing four distinct types (C1-C4 and I1-I4). These FFL types are experimentally observed to occur with varied frequencies, C1 and I1 being the abundant ones. Here we present a stochastic framework singling out the absolute value of the normalized covariance of X and Y to be the determining factor behind the abundance of FFLs while considering differential promoter activities of X and Y. Our theoretical construct employs two possible signal integration mechanisms (additive and multiplicative) to synthesize Y while steady-state population level of S remains fixed or becomes tunable reflecting two possible environmental signaling scenarios. Our model categorically points out that abundant FFLs exhibit higher amount of the designated metric which has a biophysical connotation of extrinsic noise for the target gene Y. Our predictions emanating from an overarching analytical expression utilizing biologically plausible parametric conditions are substantiated by stochastic simulation.