Extracellular Vesicle‐Associated RNA as a Carrier of Epigenetic Information

Abstract

Post-transcriptional regulation of messenger RNA (mRNA) metabolism and subcellular localization is of the utmost importance both during development and in cell differentiation. Besides carrying genetic information, mRNAs contain cis-acting signals (zip codes), usually present in their 5′- and 3′-untranslated regions (UTRs). By binding to these signals, trans-acting factors, such as RNA-binding proteins (RBPs), and/or non-coding RNAs (ncRNAs), control mRNA localization, translation and stability. RBPs can also form complexes with non-coding RNAs of different sizes. The release of extracellular vesicles (EVs) is a conserved process that allows both normal and cancer cells to horizontally transfer molecules, and hence properties, to neighboring cells. By interacting with proteins that are specifically sorted to EVs, mRNAs as well as ncRNAs can be transferred from cell to cell. In this review, we discuss the mechanisms underlying the sorting to EVs of different classes of molecules, as well as the role of extracellular RNAs and the associated proteins in altering gene expression in the recipient cells. Importantly, if, on the one hand, RBPs play a critical role in transferring RNAs through EVs, RNA itself could, on the other hand, function as a carrier to transfer proteins (i.e., chromatin modifiers, and transcription factors) that, once transferred, can alter the cell’s epigenome.

Marine Environmental Epigenetics

“…The regulatory role of ncRNAs involves the formation of RNA structures that facilitate the recruitment of chromatin-modifying complexes into specific chromatin regions, determining and maintaining specific epigenetic states (Holoch & Moazed 2015) (Figure 2). It has also been suggested that various classes of RNAs could be transferred horizontally across neighboring cells through extracellular vesicles, promoting environmental signal transduction, as well as potentially altering the epigenome of neighboring cells by carrying RNA-binding proteins (i.e., chromatin modifiers and transcription factors riding ncRNAs) (Di Liegro et al 2017). Interestingly, RNAs (ncRNA and mRNA) can be methylated just like DNA, and these epigenetic modifications in what is now defined as the epitranscriptome (Table 1) may be key in the regulation of ncRNAs (Esteller & Pandolfi 2017).…”

Cell-to-Cell Communication in Learning and Memory: From Neuro- and Glio-Transmission to Information Exchange Mediated by Extracellular Vesicles

“…In addition to proteins and lipids, most EVs also transport nucleic acids. In particular, EV-mediated transfer of mRNAs, long (>200 nt) non-coding RNAs (lncRNAs), and miRNAs (19-23 nucleotide non-coding RNA sequences), has been proposed as a new form of intercellular communication through which cells can influence gene expression of their neighbours at the epigenetic level [33,159]. For clarity, vesicles have been depicted in the same colour as the producing cell: yellow produced by the yellow cell (A), and light blue produced by the light blue cell (B).…”

“…They indeed rely on long-lasting modifications of chromatin structure and gene expression. Interestingly, the most important property of EVs in all the cell systems studied up to now seems to be their ability to influence the receiving cells at the level of gene expression through a variety of mechanisms, all of which can be considered epigenetic in nature [33,[204][205][206]. As mentioned, EVs contain proteins, mRNAs, long non-coding RNAs and miRNAs, all of which can affect the genetic activity of the recipient cells [207].…”

Ping-Pong—Tumor and Host in Pancreatic Cancer Progression

“…RBP also account for localization and trafficking of RNA-protein complexes in cells (115,116). Finally, the mRNA profile of Exo differs from that of cells (117), metabolic enzymes and proteins engaged in cell-cell and cell-matrix adhesion being frequently overrepresented (118)(119)(120), and possibly translated in Exo (121,122).…”

“…Importantly, miRNA with sequence motifs for sorting into ILV are efficiently transferred into Exo, some miRNA becoming undetectable in the donor cell (126,127). Most miRNA bind to a large number of mRNA and most mRNA are targeted by more than one miRNA, providing hurtles for their potential therapeutic use, aggravated by the discussed mode whereby miRNA affect target cells (117,128).…”