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

Key Points

  • 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.

Abstract

Novel classes of small and long non-coding RNAs (ncRNAs) are being characterized at a rapid pace, driven by recent paradigm shifts in our understanding of genomic architecture, regulation and transcriptional output, as well as by innovations in sequencing technologies and computational and systems biology. These ncRNAs can interact with DNA, RNA and protein molecules; engage in diverse structural, functional and regulatory activities; and have roles in nuclear organization and transcriptional, post-transcriptional and epigenetic processes. This expanding inventory of ncRNAs is implicated in mediating a broad spectrum of processes including brain evolution, development, synaptic plasticity and disease pathogenesis.

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Figure 1: Emerging classes of non-coding RNAs.
Figure 2: Non-coding RNAs mediating RNAi and RNA modifications.
Figure 3: Non-coding RNA dynamics mediate diverse nervous system processes and neurological disease states.
Figure 4: Role of non-coding RNAs in synaptic plasticity.

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Acknowledgements

The authors regret that space constraints have prevented the citation of many relevant and important references. M.F.M. is supported by grants from the US National Institutes of Health (NS071571, HD071593 and MH66290), as well as by the F.M. Kirby, Alpern Family, Mildred and Bernard H. Kayden and Roslyn and Leslie Goldstein Foundations.

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Paradigms for understanding roles played by non-coding RNAs in nervous system disorders with examples (PDF 193 kb)

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Glossary

Non-coding RNAs

(ncRNAs). RNA molecules belonging to an increasing number of different classes that function explicitly as RNAs, rather than as proteins, in a wide variety of regulatory, structural and functional processes.

Open reading frames

DNA sequences that are present between start, or initiation, codons and stop, or termination, codons. It is implied that these sequences are translated into proteins.

Chromatin

The structure of the genome in the nucleus formed by DNA, histones, non-histone proteins and associated factors that can undergo dynamic changes locally and more globally into open and closed conformations, which promote the execution of specific cellular programmes, such as transcription and DNA replication and repair.

Epigenetic mechanisms

Multilayered cellular processes that modulate gene expression and function in response to interoceptive and environmental stimuli during development, adult life and ageing, including DNA methylation, post-translational histone modifications, ATP-dependent nucleosome and higher-order chromatin remodelling, non-coding RNA deployment and nuclear reorganization.

Nuclear domains

A range of dynamically forming macromolecular nuclear assemblies found prominently in neural cells and consisting of chromatin and diverse factors involved in transcriptional and epigenetic regulation and post-transcriptional RNA processing, such as transcription factories, Cajal bodies, promyelocytic leukaemia nuclear bodies, nuclear stress bodies, nuclear speckles and paraspeckles.

Argonaute proteins

Proteins of the AGO and PIWI subfamilies that interact with microRNAs and endogenous small interfering RNAs and with PIWI-interacting RNAs, respectively, and have key roles in mediating post-transcriptional RNA silencing.

Retrotransposon

Mobile genetic element comprising a substantial proportion of the human genome transcribed into RNA intermediates and subsequently reintegrated into the genome, including LINE and SINE subclasses, such as Alu elements.

Somatic mosaicism

The presence of distinct genotypes in different somatic cells and tissues of an individual organism. Mosaicism arises from somatic mutations that can be generated by endogenous factors, such as mobile genetic elements and exogenous factors.

Bidirectional transcription

Transcription that occurs on both the positive and negative strands of DNA simultaneously, where the direction of RNA polymerase progression along each strand is either is convergent or divergent.

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Qureshi, I., Mehler, M. Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease. Nat Rev Neurosci 13, 528–541 (2012). https://doi.org/10.1038/nrn3234

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