Competing Endogenous RNAs, Non-Coding RNAs and Diseases: An Intertwined Story

Abstract

MicroRNAs (miRNAs), a class of small non-coding RNA molecules, are responsible for RNA silencing and post-transcriptional regulation of gene expression. They can mediate a fine-tuned crosstalk among coding and non-coding RNA molecules sharing miRNA response elements (MREs). In a suitable environment, both coding and non-coding RNA molecules can be targeted by the same miRNAs and can indirectly regulate each other by competing for them. These RNAs, otherwise known as competing endogenous RNAs (ceRNAs), lead to an additional post-transcriptional regulatory layer, where non-coding RNAs can find new significance. The miRNA-mediated interplay among different types of RNA molecules has been observed in many different contexts. The analyses of ceRNA networks in cancer and other pathologies, as well as in other physiological conditions, provide new opportunities for interpreting omics data for the field of personalized medicine. The development of novel computational tools, providing putative predictions of ceRNA interactions, is a rapidly growing field of interest. In this review, I discuss and present the current knowledge of the ceRNA mechanism and its implications in a broad spectrum of different pathologies, such as cardiovascular or autoimmune diseases, cancers and neurodegenerative disorders.

Keywords: cancer; cardiovascular pathologies; ceRNA mechanism; competing endogenous RNAs; miRNA; neurodegenerative disorders; non-coding RNAs.

Figure 1

Transcription and post-transcription regulation of messenger RNAs (mRNAs) can be affected by several direct and indirect mechanisms involving circular RNAs (circRNAs), pseudo-genes ($\mathsf{\Psi }$-genes) and long non-coding RNAs (lncRNAs). Some of these processes act on the transcription rate in the nucleus through the specific RNA–RNA complex, some others help the stability of mRNA molecules in the cytoplasm. Alongside this, the competing endogenous RNA (ceRNA) mechanism offers a parallel and complementary way through the same actors, protein coding and non-coding RNAs, but instead mediated by microRNAs (miRNAs).

Figure 2

Left panel: A naive situation with one miRNA: miR-A, and one target: transcript-X. Transcript-X harbors miR-A microRNA response elements (MREs) and can be post-transcriptionally regulated by miR-A. Right panel: In the same situation, a new miR-A target is added, transcript-Y. Transcript-Y harbors itself miR-A MREs and can sponge miR-A, thus leading to a reduced post-transcriptional regulation of transcript-X by miR-A through an indirect crosstalk.

Figure 3

Top left panel: Before interaction, a naive situation with one miRNA: miR-A, and one target: transcript-X, in a 1:2 proportion ratio. Transcript-X harbors one miRNA response element (MRE) per molecule. Bottom left panel: After interaction, at the steady state, 50% of transcript-X molecules are under the miRNA repressive action (whether post-transcriptional degradation or translational repression) and 50% of transcript-X molecules are not affected by miR-A control. Top right panel: Before interaction, a new miR-A target is added: transcript-Y, in the same amount of transcript-X. Transcript-Y also has the same MRE per molecule. The new ratio between miR-A and transcript-X is 1:4. Bottom right panel: After interaction, at the steady state, miRNAs are shared in the same proportion between the two transcripts’ molecules. On average, 75% of transcript-X molecules are free from miRNA regulation without any changes in the transcriptional rate of transcript-X.

Figure 4

Partial representation of regulatory interaction of lnc-myocardial infarction and associated transcript (MIAT): in ellipses, diseases are reported in bold and dysfunctions in italics; in comics, interacting ceRNAs, or influenced transcripts, are reported in italics red and miRNAs in italics blue. Different colors of ellipses are linked to different types of pathologies.