Evolving insights into RNA modifications and their functional diversity in the brain

Abstract

In this Perspective, we expand the notion of temporal regulation of RNA in the brain and propose that the qualitative nature of RNA and its metabolism, together with RNA abundance, are essential for the molecular mechanisms underlying experience-dependent plasticity. We discuss emerging concepts in the newly burgeoning field of epitranscriptomics, which are predicted to be heavily involved in cognitive function. These include activity-induced RNA modifications, RNA editing, dynamic changes in the secondary structure of RNA, and RNA localization. Each is described with an emphasis on its role in regulating the function of both protein-coding genes, as well as various noncoding regulatory RNAs, and how each might influence learning and memory.

Figure 1

In different local environments of the neuron, epitranscriptomic mechanisms can be employed independently and bidirectionally to regulate the qualitative state of RNA and effect experience-dependent changes in neuronal function in the brain. The intersection of various aspects of RNA control, within differing regions of the same cell, affords both mechanistic and spatial control over RNA metabolism. RNA trafficking within axons to the synapse is controlled by RNA-binding proteins, which recognize unique structural and sequence elements in RNAs. Protein synthesis is controlled temporally to guide protein abundance and synapse formation. Checkpoint mechanisms may be brought about by RNA modifications, which have already been demonstrated to regulate RNA decay. Each of these are interconnected and therefore substantially increase the complexity of RNA regulation in neurons.

Figure 2

Projected mechanisms that can control the life of a single RNA gene, perhaps at a single-molecule level. (a) RNA-binding proteins control many facets of RNA biology. RNA–protein interactions can be controlled by chemical modifications (m6A, for example). The interplay between physical changes to RNA and protein binding is therefore complex and affords many opportunities for potential regulation (RBP: RNA-binding protein). (b) Structure switching is a key mechanism that can either inhibit or enhance protein binding. (c) Schematic demonstrating N⁶-methylation of adenosine, which has been shown to lead to RNA decay. (d) RNA editing can result in the expression of an altered protein. This figure demonstrates A-to-I editing, which can alter codon identity, leading to a protein with an altered sequence.