Molecular dynamics of ceRNA interactions. (A) Optimal molecular conditions for effective ceRNA crosstalk depend on miRNA/ceRNA ratios. Schematic representation of a simplified ceRNA network involving two transcripts (with blue backbones) harboring two different MRE sites (orange and green circles) that bind to miRNA1 (orange) and miRNA2 (green), respectively. Variations in ceRNA expression levels would generate a response in the expression of co-regulated ceRNAs only in a narrow miRNA concentration window, and only for a range of ceRNA concentration. When miRNA concentration is in excess, the titration capacity of competing MRE is diminished and no effect would be observed on ceRNA crosstalk. Conversely, in excess of ceRNA, most miRNA molecules will bind their MRE sites, and the system would be insensitive to changes in the relative miRNA/ceRNA ratios. (B) The presence of indirect interactions can amplify ceRNA crosstalk. Schematic representation of two ceRNA networks involving three ceRNAs and two (top panel) or three (bottom panel) miRNAs. When ceRNA 2 is able to co-regulate ceRNA 3 by sequestering miRNA 3, the effect of ceRNA 1 upregulation on ceRNA 2 and ceRNA 3 levels may be amplified by this secondary crosstalk. This is termed an indirect interaction as it does not involve a direct relationship between ceRNA 1 and either ceRNA 2 or ceRNA 3.