MicroRNA in Control of Gene Expression: An Overview of Nuclear Functions

Abstract

The finding that small non-coding RNAs (ncRNAs) are able to control gene expression in a sequence specific manner has had a massive impact on biology. Recent improvements in high throughput sequencing and computational prediction methods have allowed the discovery and classification of several types of ncRNAs. Based on their precursor structures, biogenesis pathways and modes of action, ncRNAs are classified as small interfering RNAs (siRNAs), microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), endogenous small interfering RNAs (endo-siRNAs or esiRNAs), promoter associate RNAs (pRNAs), small nucleolar RNAs (snoRNAs) and sno-derived RNAs. Among these, miRNAs appear as important cytoplasmic regulators of gene expression. miRNAs act as post-transcriptional regulators of their messenger RNA (mRNA) targets via mRNA degradation and/or translational repression. However, it is becoming evident that miRNAs also have specific nuclear functions. Among these, the most studied and debated activity is the miRNA-guided transcriptional control of gene expression. Although available data detail quite precisely the effectors of this activity, the mechanisms by which miRNAs identify their gene targets to control transcription are still a matter of debate. Here, we focus on nuclear functions of miRNAs and on alternative mechanisms of target recognition, at the promoter lavel, by miRNAs in carrying out transcriptional gene silencing.

Keywords: epigenetics; miRNA inducing silencing complex (miRISC); microRNA; nuclear function; transcriptional control.

Figure 1

Examples of alternative mechanisms of miRNA guided transcriptional gene activation (TGA). (A) Long non coding RNAs (lncRNAs) or promoter associated RNAs (pRNAs) can silence gene expression by recruiting a transcriptional repressive complex. miRNAs targeting a complementary sequence within the lncRNA or pRNA would recruit a nuclear RISC and induce cleavage of the antisense lncRNA or pRNA transcript promoting exclusion of repressive complex and derepression of the sense transcription; (B) Alternatively, miRNAs induce gene activation by recruiting a protein complex consisting of transcriptional activators. TNRC6A, Trinucleotide repeat-containing 6A; TRBP, trans-activation response RNA-binding protein; AGO, Argonaute; TF, Transcription Factor.

Figure 2

Examples of alternative mechanisms of miRNA guided transcriptional gene silencing (TGS). miRNAs can inhibit gene expression at transcriptional level. (A) In this case, miRNA-targeted non-coding promoter associated RNA would represent a docking platform for a protein inhibitory complex consisting of elements of RISC, PcG proteins and chromatin modulators. This interaction would enable a protein inhibitor complex to be in close proximity of the targeted promoter region, the chromatin structure of which would be modified to establish a non-permissive transcriptional status; (B) Alternatively, miRNA guided recognition and interaction with promoter regions may occur through a direct interaction between RNA and single-stranded DNA complementary sequences. DNMTs, DNA methyltransferases; HDAC, Histone deacetylase; AGO, Argonaute; EZH2, Enhancer of zeste homolog 2; Transcriptional Factor, TF; RNA Polymerase II, RNApolII.

Figure 3

Schematic representation of the function of miRNAs in the nucleus. Nuclear miRNAs may activate (TGA) or inhibit (TGS) gene transcription, block maturation of non-coding RNAs (LncRNA, pri-miRNA, pre-miRNA), affect alternative splicing (orange arrow); more controversial is miRNAs function in the nucleolus where they might affect maturation of ribosomal RNAs (rRNAs) and of messenger RNA (mRNAs) (orange arrow). pri-miRNA, primary miRNA; pre-miRNA, precursor miRNAs; miRISC, miRNA inducing silencing complex.