Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease

Abstract

Recent studies have revolutionized our understanding of the architecture of the eukaryotic genome, which is transcribed pervasively in sense and antisense orientations, forming a universe of non-coding RNAs (ncRNAs) that are encoded in overlapping and interleaved patterns relative to protein-coding genes and to other ncRNAs. This evolving ncRNA landscape includes many recently characterized classes and subclasses of long and small ncRNAs, each with specific biogenesis and effector pathways. These ncRNAs can have diverse roles in epigenetic, transcriptional and post-transcriptional regulatory processes by engaging in sequence-selective and conformational interactions with DNA, RNA and protein molecules. The brain exhibits particularly complex developmental stage-, region-, cell type-, subcellular compartment- and stimulus-specific profiles of ncRNA expression, post-transcriptional modifications, transport and functioning that are highly integrated into the known molecular circuitry underlying key neurobiological processes, including neural patterning, neural stem cell maintenance and differentiation, synaptic development and plasticity, brain ageing and homeostasis and stress responses. Elucidating the pathogenic mechanisms for nervous system disorders must account for the potential roles of ncRNAs. Here, we highlight non-mutually exclusive paradigms for doing so, such as identifying mutations in ncRNA genes; variations in protein-coding genes that disrupt their interactions with ncRNAs; epigenetic deregulation of ncRNAs; perturbations in ncRNA pathways; ncRNA–disease relationships by genomic context; and interrogating central and peripheral tissues for deregulation of ncRNAs.