RNA-mediated gene activation

Abstract

The regulation of gene expression by non-coding RNAs (ncRNAs) has become a new paradigm in biology. RNA-mediated gene silencing pathways have been studied extensively, revealing diverse epigenetic and posttranscriptional mechanisms. In contrast, the roles of ncRNAs in activating gene expression remains poorly understood. In this review, we summarize the current knowledge of gene activation by small RNAs, long non-coding RNAs, and enhancer-derived RNAs, with an emphasis on epigenetic mechanisms.

Keywords: RNAa; eRNA; enhancer; epigenetic; lincRNA; non-coding RNA; saRNA; transcriptional activation.

Figure 1. Small RNA-mediated gene activation (A) and derepression (B). In (A), a small RNA (green) targets an Argonaute protein to a promoter-associated ncRNA. This can result in the recruitment of various chromatin modifying complexes and hnRNPs, which together mediate the transcriptional activation of the nearby gene. Importantly, although not shown here, chromosomal looping mechanisms may allow small RNA-Argonaute complexes to regulate promoter activity without directly binding to the promoter region. In (B), an antisense transcript recruits epigenetic silencers to the sense gene promoter, repressing sense gene expression. A small RNA-Argonaute complex downregulates the antisense transcript through a classical RNAi pathway, resulting in its degradation and derepressing sense gene expression. Silencing chromatin marks are lost, and the general transcriptional machinery is recruited.

Figure 2. LincRNA-mediated gene activation. (A) Transcription of a lincRNA gene with a typical chromatin signature, consisting of an H3K4 trimethylated promoter and a H3K36 trimethylated gene body. (B) The lincRNA may act in cis or in trans, to recruit epigenetic activators to specific genomic regions. Locus specificity may arise from partial complementarity to the lincRNA primary sequence, whereas recruitment of the protein machinery may be more dependent on secondary RNA structures.

Figure 3. eRNA-mediated gene activation. (A) In the example shown here, eRNA-mediated gene activation occurs following a ligand binding to a nuclear receptor. (B) The activated receptor dissociates from the membrane and acts as a transcription factor, where it binds to an enhancer region and induces the production of bidirectional eRNAs. (C) These eRNAs may lead to increased intrachromosomal interactions with distal promoters, possibly through the Mediator and Cohesin protein complexes. The physical proximity of the enhancer region and/or eRNAs to targeted promoters leads to transcriptional upregulation.