Pseudogenes regulate parental gene expression via ceRNA network

Abstract

The concept of competitive endogenous RNA (ceRNA) was first proposed by Salmena and colleagues. Evidence suggests that pseudogene RNAs can act as a 'sponge' through competitive binding of common miRNA, releasing or attenuating repression through sequestering miRNAs away from parental mRNA. In theory, ceRNAs refer to all transcripts such as mRNA, tRNA, rRNA, long non-coding RNA, pseudogene RNA and circular RNA, because all of them may become the targets of miRNA depending on spatiotemporal situation. As binding of miRNA to the target RNA is not 100% complementary, it is possible that one miRNA can bind to multiple target RNAs and vice versa. All RNAs crosstalk through competitively binding to miRNAvia miRNA response elements (MREs) contained within the RNA sequences, thus forming a complex regulatory network. The ratio of a subset of miRNAs to the corresponding number of MREs determines repression strength on a given mRNA translation or stability. An increase in pseudogene RNA level can sequester miRNA and release repression on the parental gene, leading to an increase in parental gene expression. A massive number of transcripts constitute a complicated network that regulates each other through this proposed mechanism, though some regulatory significance may be mild or even undetectable. It is possible that the regulation of gene and pseudogene expression occurring in this manor involves all RNAs bearing common MREs. In this review, we will primarily discuss how pseudogene transcripts regulate expression of parental genes via ceRNA network and biological significance of regulation.

Keywords: ceRNA; gene expression; microRNA; pseudogene.

Figure 1

A balance between protein‐coding genes and pseudogenes (ceRNA). (A) In the context of little or no pseudogene transcription, expression of protein‐coding genes is significantly repressed by miRNAs that would normally be shared by all transcripts (ceRNA) but are now mainly absorbed by protein‐coding genes; (B) All transcripts constitute a balanced network in which protein‐coding genes are appropriately expressed; (C) When pseudogenes(ceRNA) are spatially and temporally overexpressed, pseudogene transcripts (ceRNA) absorb most miRNAs and released repression of protein‐coding genes. As a result, expression of the parental genes is significantly increased.

Figure 2

Interactions between ceRNAs via miRNAs. Transcripts A and B, such as parental genes and pseudogenes, share the common miRNA‐a, and would have a strong regulatory effect on each other. In contrast, transcripts A and C do not share the same miRNA, but they have indirect contact via transcript B, so transcript A and C would have a weak regulatory effect on each other. If A dominantly adsorbs miRNA‐a, so B will be able to adsorb more miRNA‐b. As a result, repression of miRNA‐b on C will be reduced. Thus, a regulatory interaction between A and C will occur via a ceRNA chain. As an extention, the farther distance between ceRNAs in the chain, the weaker the regulatory effect would be on each other. Further complexity is added by imperfect complementary binding between miRNAs and diverse MREs located on ceRNAs in the entire network.

Figure 3

Formation of a ceRNA network. As proposed by Salmena et al. 3, all transcriptional RNAs may form an entire network via miRNAs in a given cell. Pseudogene transcripts constitute a part of this entire network and play regulatory roles in controlling parental gene expression. As each ceRNA transcript may have more than one MREs and each miRNA may have multiple target sites, a ceRNA network will form via interaction between miRNAs and long RNAs.