Dogma derailed: the many influences of RNA on the genome

Abstract

Epigenetic control of gene expression is a critical component of transcriptional regulation. Remarkably, the deposition of epigenetic modifications is often guided by noncoding RNAs. Although noncoding RNAs have been most often implicated in posttranscriptional gene silencing, these molecules are now emerging as critical regulators of gene expression and genomic stability at the transcriptional level. Here, we review recent efforts to understand the mechanisms by which RNA controls the expression or content of DNA. We discuss the role of both small RNAs and long noncoding RNAs in directing chromatin changes through histone modifications and DNA methylation. Furthermore, we highlight the function of RNA in mediating DNA cleavage during genome rearrangements and pathogen defense. In understanding the mechanisms of RNA control over DNA, the power of RNA may one day be harnessed to impact gene expression in a therapeutic setting.

Figure 1. Parallels in Small RNA-Mediated Chromatin Effects

DNA silencing or cleavage is initiated by the biogenesis of small RNAs from host-encoded precursors, which are then bound by effector proteins and lead to the transcriptional silencing or elimination of complementary sequences. Orthologs are indicated as follows: Dicers, green; RNA-dependent RNA polymerase complexes, blue; polymerases, brown; Ago clade Argonautes, yellow; Piwi clade Argonautes, purple; histone and DNA methyltransferases, orange; and chromodomain-containing proteins, gray. Epigenetic modifications are represented as follows: H3K9me, blue; H3K27me, orange; and DNA methylation, green. The targets of small RNA-mediated TGS in each organism are indicated in the right panels.

Figure 2. Effects of lncRNAs at the Chromatin Level

lncRNAs interact with several activating and repressive chromatin-modifying complexes. Representative lncRNAs are grouped according to the protein complex with which they interact. Depending on the lncRNA, genomic targeting of these chromatin modifiers can occur in cis or in trans.

Figure 3. Small RNA-Mediated Genome Defense

Foreign transposable and repetitive sequences, represented by blue, green, and red segments, are present in the genomes of mammals, insects, and ciliates. Mammals and Drosophila utilize piRNAs to silence active transposons, either by DNA methylation or by repressive histone modifications (gray circles). In Tetrahymena and Paramecium, scnRNAs recognize IES regions, which include mobile genetic elements, and guide their genomic excision by marking them with repressive histone modifications. Oxytricha eliminates IES sequences using an orthogonal mechanism; piRNAs correspond to the retained sequences (black). Chromatin modifications that guide this process have not yet been identified. Bacteria and archaea incorporate sequences from foreign pathogens or plasmids (colored segments) into CRISPR loci. Expression of crRNAs from these loci results in cleavage of infecting bacteriophages and plasmid DNA.