Figure 2.

Schemes of feedforward loops (FFLs). Lines ending with an arrow indicate activation, whereas T ending lines indicate repression. Simple straight lines indicate that the interaction can either be activatory or repressive. (a) On the left, the general scheme of an FFL is represented. The master regulator gene A regulates gene C both directly (left path) and indirectly (right path) through the direct regulation of gene C. The central and right schemes synthesize all possible miRNA mediated FFLs: the miRNA can either play the role of a master regulator or standing in the intermediate regulator position. (b–d) Coherent miRNA mediated feedforward loops (cFFLs): regulatory paths make an overall positive sign. In (b) and (c), the TF plays the role of the master regulator, while in (d), such a role is assumed by the miRNA. (e,f) Incoherent miRNA mediated feed-forward loops (iFFLs): regulatory paths make an overall negative sign. In (e), the TF acts as the master regulator by activating both the miRNA and the target; in (f), the master regulator is the miRNA that represses both its targets. One of the targets then represses the other one. (g–j) Experimental examples of miRNA mediated cFFLs. (g) Two FFLs regulating the “all-or-none” expression of two groups of type 1 specific genes in human epithelial tumour cells. Adapted from [105]. (h) FFL mediated by miR-27a/b-3p regulating the expression of two target genes (PPARG and SCAMP3) in adipogenesis. The expression of PPARG upregulates SCAMP3. Adipogenesis has been found to be positively regulated by PPARG (grey arrow) and negatively regulated by PPARG (T-ended grey line). Adapted from [104]. (i) miRNA mediated FFL that fine tunes G0/G1-S transition during the cell cycle: the miR-17 family regulates both E2F1 and RB1, whose expression inhibits E2F1. Adapted from [117]. (j) Oncogenic transformation is regulated by miRNA let-7 through a cFFL: NF-$\kappa$B regulates IL6 directly and indirectly through let-7. A feedback is present between IL6 and NF-$\kappa$B. Adapted from [52]. (k–m) Experimental examples of miRNA mediated incoherent feed-forward loops (iFFLs). (k) iFFL that controls proliferative signal: the proto-oncogene c-MYC directly controls E2F1 transcription and indirectly controls its translation through activation of miR-17 and miR-20a. Adapted from [118] (l) miR-263a controls cell crowding in the fly retina development, by regulating the pro-apoptotic gene head involution defective (hid) both directly and indirectly through the RAS/MAPK pathway. Adapted from [119]. (m) The miRNA lin-4 dampens expression oscillations of its target miRNA lin-14 through an FFL where both miRNAs are synchronously transcribed by a pulsatile source S. Adapted from [120]. (n) General scheme of an miRNA mediated intronic self-loop.