Interplay between RNA interference and transposable elements in mammals

Abstract

RNA interference (RNAi) plays pleiotropic roles in animal cells, from the post-transcriptional control of gene expression via the production of micro-RNAs, to the inhibition of RNA virus infection. We discuss here the role of RNAi in regulating the expression of self RNAs, and particularly transposable elements (TEs), which are genomic sequences capable of influencing gene expression and disrupting genome architecture. Dicer proteins act as the entry point of the RNAi pathway by detecting and degrading RNA of TE origin, ultimately leading to TE silencing. RNAi similarly targets cellular RNAs such as repeats transcribed from centrosomes. Dicer proteins are thus nucleic acid sensors that recognize self RNA in the form of double-stranded RNA, and trigger a silencing RNA interference response.

Keywords: Dicer (Dicer1); RNA interference; epigenetics; mammals; pathogen-associated molecular pattern (PAMP); pattern recognition receptor (PRR); transposable elements.

Figure 1

RNA interference in mammals. Left, post-transcriptional regulation of gene expression by RNAi. Pri-miRNAs, produced by genomic transcription, are processed into pre-miRNAs by the Microprocessor complex, composed of Drosha and Dgcr8. After shuffling to the cytoplasm, pre-miRNAs are cleaved by Dicer to generate mature miRNAs of 22 nucleotides in length on average. Loaded into RISC containing the endonuclease Ago, miRNAs guide the sequence-specific interaction with mRNAs to inhibit translation, resulting in mRNA degradation. Mismatch(s) between miRNA and mRNA sequences prevent degradation of mRNAs by Ago2. Right, expression of TEs, or RNA virus infection, lead to the cytosolic accumulation of dsRNA, which is processed by Dicer proteins, giving rise to siRNAs that guide cognate RNA degradation (no mismatch, Ago2 endonuclease is active). TEs are mainly composed of ERVs, LINEs and SINEs. ERVs may encode the ORFs Gag, Pol and Env, delimited by LTRs, while LINEs encode two ORFs. SINEs do not encode any functional ORFs and rely instead on LINE proteins for cycle completion.