Regulation of histone methylation by noncoding RNAs

Abstract

Cells can adapt to their environment and develop distinct identities by rewiring their transcriptional networks to regulate the output of key biological pathways without concomitant mutations to the underlying genes. These alterations, called epigenetic changes, persist stably through mitotic or, in some instances, meiotic cell divisions. In eukaryotes, heritable changes to chromatin structure are a prominent, but not exclusive, mechanism by which epigenetic changes are mediated. These changes are initiated by sequence-specific events, which trigger a cascade of molecular interactions resulting in feedback mechanisms, alterations in chromatin structure, histone posttranslational modifications (PTMs), and ultimately establishment of distinct transcriptional states. In recent years, advances in next generation sequencing have led to the discovery of several novel classes of noncoding RNAs (ncRNAs). In addition to their well-established cytoplasmic roles in posttranscriptional regulation of gene expression, ncRNAs have emerged as key regulators of epigenetic changes via chromatin-dependent mechanisms in organisms ranging from yeast to man. They function by affecting chromatin structure, histone PTMs, and the recruitment of transcriptional activating or repressing complexes. Among histone PTMs, lysine methylation serves as the binding substrate for the recruitment of key protein complexes involved in the regulation of genome architecture, stability, and gene expression. In this review, we will outline the known mechanisms by which ncRNAs of different origins regulate histone methylation, and in doing so contribute to a variety of genome regulatory functions in eukaryotes.

Keywords: Epigenetics; Histone methylation; Noncoding RNA; lncRNA; piRNA; siRNA.

Figure 1

Small RNA-directed histone methylation. (A) siRNAs derived from processing of endogenous dsRNAs transcripts are loaded onto Argonaute proteins. Ago:siRNA complexes recognize complementary chromatin-associated transcripts by base-pairing interactions and binding to H3K9me via Chp1 component of RITS and target the recruitment of lysine methyltransferase (KMT) to the genome via direct protein-protein interactions. Iterative cycles of dsRNA generation in organisms which possess RNA-dependent RNA polymerases (RdRPs) leads to a positive feedback loop which amplifies the dsRNA/siRNA signal and reinforces H3K9me in a sequence-specific manner (B) Similar to above, piRNAs recognize transposable element (TE)-derived RNAs to promote methylation of TE loci in gonadal (and maybe somatic) tissues. Instead of RdRPs, ‘Ping-Pong’ cycles of cleavage activity by different Piwi clade members of the Argonaute family amplify the piRNA signal. Primary antisense piRNA clusters generate the complementary RNAs used in feed forward loop. piRNA:Piwi complexes target H3K9me to TEs in a sequence-specific manner, but whether this is through direct protein-protein interactions, by a linker protein, or other means remains undetermined. Small circles above nucleosomes represent methylated histone tails.

Figure 2

Models of lncRNA-mediated histone methylation. (A) RNA Pol II-mediated transcription of lncRNAs leads to the recruitment of KMTs, and alterations in histone methylation within the transcriptional unit of the lncRNA itself. In these instances, lncRNAs are not directly involved in KMT recruitment; instead their transcription results in recruitment of chromatin-regulatory complexes that alter local chromatin structure and regulate the transcription of neighboring genes in cis. (B) Chromatin-associated lncRNAs work as specificity factors and scaffolds for the cis recruitment of multiple histone-modifying complexes, including histone methyltransferases. RNA-protein (or lncRNA:smallRNA/Ago) interactions recruit KMT complexes and lead to coordinated modification of histone tails locally. In some instances, these modifications can spread to the neighboring nontranscribed regions. Some ncRNAs are known to interact with multiple proteins by distinct binding domains. (C) lncRNAs, bound to histone-modifying complexes, target different genomic loci in trans. In some instances, lncRNAs may act both as specificity factors, and as structural components of the KMT complexes.