A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?

Abstract

Here, we present a unifying hypothesis about how messenger RNAs, transcribed pseudogenes, and long noncoding RNAs "talk" to each other using microRNA response elements (MREs) as letters of a new language. We propose that this "competing endogenous RNA" (ceRNA) activity forms a large-scale regulatory network across the transcriptome, greatly expanding the functional genetic information in the human genome and playing important roles in pathological conditions, such as cancer.

Figure 1. Flipping the conventional logic of microRNA-mRNA interactions

How mRNAs affect microRNAs is less well characterized than how of microRNAs affect effect mRNAs. A. The relationship between mRNAs and microRNAs could be reciprocal (Seitz 2009), causing the level of one mRNA to influence the level and activity of another mRNA. B. Thus, RNA molecules could communicate with each other through microRNA and microRNA recognition sequences (MREs). The greater the number of shared MREs, the greater the level of “communication” and thus co-regulation. C. The 3’ UTRs of RNA molecules contain MREs, which can function in cis to regulate the RNA molecule itself but also possibly in trans to regulate levels of microRNAs and consequently other RNAs.

Figure 2. MicroRNA effectiveness is influenced by the cellular concentration of its MREs

Multiple RNA transcripts can contain MREs for the same microRNA. Upregulation of any of these RNA transcripts increases the cellular concentration of a particular MRE, which could decrease levels of transcripts targeted by the same microRNA.

Figure 3. Potential pathological alterations of cellular ceRNA

Many types of genetic events can alter the abundance or sequence of a particular transcript. Under the ceRNA hypothesis, these events could induce ‘coding-independent’ effects, by altering the levels of microRNAs available for silencing particular transcripts.