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The m6A epitranscriptome: transcriptome plasticity in brain development and function

Abstract

The field of epitranscriptomics examines the recently deciphered form of gene expression regulation that is mediated by type- and site-specific RNA modifications. Similarly to the role played by epigenetic mechanisms — which operate via DNA and histone modifications — epitranscriptomic modifications are involved in the control of the delicate gene expression patterns that are needed for the development and activity of the nervous system and are essential for basic and higher brain functions. Here we describe the mechanisms that are involved in the writing, erasing and reading of N6-methyladenosine, the most prevalent internal mRNA modification, and the emerging roles played by N6-methyladenosine in the nervous system.

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Fig. 1: m6A-mediated RNA regulation and physiological effects.
Fig. 2: m6A regulation of gene expression.
Fig. 3: m6A in neurogenesis.
Fig. 4: Differential localization of methylated transcripts in cellular compartments.
Fig. 5: m6A in peripheral nerve regeneration.

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Acknowledgements

The authors thank the Kahn Family Foundation for continuous support of their research. D.D is supported by grants from the Israel Science Foundation (2494/18 and 2625/17) and the Human Frontier Science Program (CDA 00048/2018). G.R. and D.D are supported by the German–Israeli Project Cooperation (DIP) of the German Federal Ministry of Education and Research.

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D.D. and S.M-M. researched the data for the article, wrote and edited the manuscript before submission. G.R, N.A. and D.D. contributed substantially to discussions of the content. D.D., I.L., S.M.-M. and G.R. contributed to writing the article.

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Correspondence to Dan Dominissini.

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Glossary

Epigenetic modifications

Covalent chemical modifications to DNA or histones that affect nucleosome positioning, DNA packaging and/or chromatin accessibility to provide spatial and temporal control of gene expression without altering the DNA sequence. These marks are stable and heritable, but can be removed by dedicated enzymes to provide dynamic regulation.

Recognition elements

Chemically modified cis-acting elements that consist of specific nucleotide sequences or certain folded structures that can modulate the binding capacity of RNA-binding proteins.

Internal mRNA modification

A chemical modification of the nucleotides in an mRNA transcript, excluding the 5′ cap structure.

Phase separation

The process by which fibrils, hydrogels or liquid droplets are formed by low-complexity amino acid sequences. Physically, the process involves two solutes demixing to form two new phases of different composition.

Processing bodies

(P bodies). Cytoplasmic membraneless RNA granules that dynamically store translationally inactive messenger ribonucleoproteins, similar to stress granules. P bodies can exist in the absence of stress and house proteins that promote mRNA decay and translational repression. Repressed messenger ribonucleoproteins can exit processing bodies and re-enter translation in the cytoplasm.

Translation initiation factor

A protein that participates in the initiation stage of translation by guiding the recruitment, scanning and assembly of the 80S ribosome at the start codon of mRNA transcripts.

Stress granules

Membraneless cytoplasmic aggregates of translationally inactive messenger ribonucleoproteins — composed of stalled preinitiation complexes, ribosomal subunits, translation initiation factors and mRNAs — that form in response to acute stress. Their formation and dissolution support proteome modulation during changing environmental conditions.

Developmental competence

The ability of progenitors to appropriately respond to inductive differentiation cues towards specific lineages and follow the full spectrum of developmental trajectories: that is, to proliferate, differentiate and give rise to all possible progeny. During differentiation, stem cells commit to specific developmental pathways and lose competence to take on others.

Pluripotency

A capacity of stem cells to differentiate into the three primary germ cell layers of the embryo (but not into extraembryonic tissues) and to self-renew by division.

Induced pluripotent stem cell

A terminally differentiated somatic cell that has been reprogrammed back to an embryonic pluripotent stem cell-like state by the introduction of a set of pluripotency-related transcription factors in vitro. This technology provides an unlimited source of any cell for research and therapeutic applications.

Organoids

Miniature, simplified three-dimensional versions of organs that are derived from stem cells.

Long-term potentiation

A form of activity-dependent plasticity in which transient high-frequency stimulation produces a rapid and persistent increase in synaptic strength (transmission efficacy). Multiple forms of long-term potentiation exist, depending, among other variables, on the type of synapse, the nature of the stimulation and the developmental stage. It is thought to be a cellular mechanism underlying learning and memory.

Fear conditioning

An associative form of learning in which pairing a neutral stimulus (as a particular context or cue) with an aversive event causes the former to acquire aversive properties and the ability to elicit fear responses when presented alone in a novel context (cued fear test) or by re-exposure to the conditioning context (contextual fear test).

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Livneh, I., Moshitch-Moshkovitz, S., Amariglio, N. et al. The m6A epitranscriptome: transcriptome plasticity in brain development and function. Nat Rev Neurosci 21, 36–51 (2020). https://doi.org/10.1038/s41583-019-0244-z

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