Figure 1.
Propagation of perturbation effects through coregulation and target sharing. (A) Mutual effects between mRNAs competing for binding the same miRNA regulator (competing endogenous mRNAs). R1 is a miRNA that negatively regulates its targets T0 and T2 (A a). Upon knockdown of T0 (A b), more R1 molecules are freed (A c). The freed R1 molecules interact with T2, exerting greater regulatory effect on T2. As a result, the level of free T2 molecules is further decreased (A c). Thus, the change in T0 level affects T2 level through their common regulator. Rectangles correspond to miRNA regulators and circles correspond to target mRNAs. The intensity of node color and the direction of the arrow within the node mark the direction of change in expression. The thickness of the edge marks the strength of the regulation. (B) Mutual effects between miRNAs over binding to a shared target (competing endogenous miRNAs). R0 and R2 are two miRNAs that negatively regulate T1 (B a). Overexpression of R0 (B b) leads to downregulation of T1 (B c). As a result, the level of free R2 molecules increases (B c). (C) Propagation of perturbation effect. R1 and R3 are two miRNAs that negatively regulate (T0, T2) and (T2, T4), respectively (C a). T2 is a shared target of R1 and R3. Knockdown of T0 (C b) increases the level of free R1 molecules (C c). The freed R1 molecules bind T2, further downregulating T2 (C c). The decrease in T2 level frees more R3 molecules to focus on T4, which, in turn, is further downregulated (C d). In such a case, there is a propagation of the effect of T0 knockdown to T4 through T2, the shared target of R1 and R3. Note that in rows A–C, the index of the perturbed node (source) is 0 and regulator and target nodes are not indexed separately but interchangeably, by their distance from the source.