Rapid and dynamic transcriptome regulation by RNA editing and RNA modifications

Abstract

Advances in next-generation sequencing and mass spectrometry have revealed widespread messenger RNA modifications and RNA editing, with dramatic effects on mammalian transcriptomes. Factors introducing, deleting, or interpreting specific modifications have been identified, and analogous with epigenetic terminology, have been designated "writers," "erasers," and "readers." Such modifications in the transcriptome are referred to as epitranscriptomic changes and represent a fascinating new layer of gene expression regulation that has only recently been appreciated. Here, we outline how RNA editing and RNA modification can rapidly affect gene expression, making both processes as well suited to respond to cellular stress and to regulate the transcriptome during development or circadian periods.

Figure 1.

Rapid modifications of the epitranscriptome in response to extracellular inputs. RNA modifications and editing can regulate the transcriptome. Both types of epitranscriptomic regulation are particularly suited to modulate the transcriptome in situations of stress because they allow a more rapid response compared with classic regulation mechanisms of gene expression.

Figure 2.

The dynamic interplay of factors writing, reading, and erasing m6A modifications. The m6A mark is written by METTL3 or METTL14 (blue) in complex with WTAP (purple), whereas the proteins ALKBH5 or FTO (red) are erasers of m6A modifications. Several reading mechanisms have been characterized: (1) YTHDF proteins (green) can detect the m6A mark and shift localization of the transcripts to P-bodies and thereby promote degradation; (2) m6A can cause structural changes and thereby lead to differential binding of RNA-binding proteins (RBP, green); (3 and 4) HNRNPA2B1 (green) can bind to m6A sites in pri-miRNAs or pre-mRNAs and either promote maturation of miRNAs (3) or cause alternative splicing (4); and finally, (5) under stress conditions, m6A can also cause cap-independent translation. m6A writing mechanisms are in blue, reading mechanisms are in green, and erasing mechanisms are in red.

Figure 3.

The consequences of A-to-I-editing are diverse. (A) Editing sites in protein-coding transcripts are frequently defined by double-stranded structures between exons and introns. The extent of editing can have various consequences. In the case of the glutamate receptor subunit GRIA2, it influences the receptor permeability for Ca²⁺ ions. (B) A-to-I editing can affect miRNA biogenesis and interfere with DROSHA or DICER cleavage, as well as alter target specificity of miRNAs. Editing sites are marked in red; arrows point to the editing site. (C) Unedited foreign dsRNA is sensed by MDA5 (purple) and promotes the interferon response via MAVS (blue). Edited dsRNA does not activate the interferon response and is treated as self.