RNA-mediated epigenetic regulation of gene expression

Small RNAs, which function within Argonaute (AGO) complexes that target nascent transcript scaffolds, and long non-coding RNAs (lncRNAs), or even mRNAs, that themselves act as chromatin-associated scaffolds recruit chromatin-modifying activities to mediate stable changes in gene expression.Small RNAs maintain a persistent memory of epigenetic silencing by forming positive feedback loops with chromatin-based signals. These self-reinforcing loops are best understood in the pericentromeric heterochromatin of Schizosaccharomyces pombe and the RNA-directed DNA methylation pathway of Arabidopsis thaliana.In Drosophila melanogaster, recent evidence suggests the existence of a self-reinforcing relationship between Piwi-interacting RNA (piRNA) biogenesis and histone H3 lysine 9 (H3K9) methylation at piRNA source loci. In mice, piRNAs direct DNA methylation, but these signals do not seem to form a self-reinforcing loop.In Caenorhabditis elegans, the AGO protein HRDE-1 maintains heritable silencing of foreign sequences after recognition by the piRNA pathway, while the AGO protein CSR-1 protects 'self' sequences from silencing.Numerous lncRNAs have been proposed to directly recruit the Polycomb repressive complex 2 (PRC2) histone methyltransferase, but a lack of specificity in PRC2–RNA interactions suggests a more complicated picture.The well-studied lncRNA X inactive specific transcript X (XIST) spreads along the inactive X chromosome and mediates gene silencing by recruiting PRC2. Recent studies show that this occurs indirectly through the RNA-binding protein JARID2.lncRNAs transcribed from enhancer regions can activate gene expression by acting as scaffolds that bring enhancer and promoter regions into proximity, while also recruiting co-activators to modify histones.The mRNAs of meiotic genes in S. pombe are silenced during vegetative growth in a process that involves (but does not require) recruitment of H3K9 methylation activity by the mRNA transcripts themselves. This mechanism may represent an ancestral step in the evolution of lncRNAs, in which RNAs have acquired a scaffold function to recruit histone modifiers but have not yet lost protein-coding potential.