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Epitranscriptomics: A New Regulatory Mechanism of Brain Development and Function

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Review

Epitranscriptomics: A New Regulatory Mechanism of Brain Development and Function

Florian Noack et al. Front Neurosci.

Abstract

Epigenetic modifications of DNA and chromatin are long known to control stem cell differentiation and organ function but the role of similar modifications at the level or regulatory RNAs is just beginning to emerge. Over 160 RNA modifications have been identified but their abundance, distribution and functional significance are not known. The few available maps of RNA modifications indicated their dynamic regulation during somatic stem cell differentiation, brain development and function in adulthood suggesting a hitherto unsuspected layer of regulation both at the level of RNA metabolism and post-transcriptional control of gene expression. The advent of programmable, RNA-specific CRISPR-Cas editing platforms together with the identification of RNA modifying enzymes now offers the opportunity to investigate the functional role of these elusive epitranscriptome changes. Here, we discuss recent insights in studying the most abundant modifications in functional mRNAs and lncRNAs, N6-methyladenosine and 5-(hydroxy-)methylcytosine, and their role in regulating somatic stem cell differentiation with particular attention to neural stem cells during mammalian corticogenesis. An outlook on novel CRISPR-Cas based systems that allow stem cell reprogramming by epitranscriptome-editing will also be discussed.

Keywords: 5-hydroxymethylcytosine; 5-methylcytosine; N6-methyladenosine; RNA-epigenetics; brain development; epitranscriptome-editing; epitranscriptomics; neural stem cells.

Figures

Figure 1
Figure 1
Drawings of N6-methyladenosine (left) or 5-methylcytosine (right) pathways. Left: Adenosine is methylated (m6A, green) by the METTL3/METTL14/WTAP complex or removed by the FTO or ALKBH5 demethylases. Proteins can bind m6A directly (YTH and eIF3, orange and gray respectively), indirectly through changes in secondary structure (HNR, dark blue) or be repelled by m6A (HUR, purple). Right: Cytosine is methylated at the 5 position (5mC, red) by NSUN2 and oxidized to 5-hydroxymethyl- (5hmC) or 5-formylcytosine (light blue) by TET proteins. 5mC can recruit ALYREF (orange) decreasing translation efficiency, while 5hmC can enhance translation (red and green arrows, respectively). APOBEC1 and SMUG1 (yellow) may be involved in the removal of oxidized 5-methylcytosine resulting in the degradation of the cleaved mRNA. Potential functions of m6A or 5mC readers are indicated in brackets.
Figure 2
Figure 2
Possible uses of the CRISPR-dCas13 (gray) system for epitranscriptome editing of N6-methyladensosine (m6A, top) or 5-methylcytosine (5mC, bottom). Top: Fusing dCas13 together with METTL3 (green) or FTO (white) may allow the site and transcript specific methylation (green) or demethylation (white) of mRNA, respectively resulting in m6A-mediated changes in translation or RNA stability (red or green arrows). Bottom: methylation of cytosine (red) or oxidation of 5mC (blue) of cytosine can be triggered by dCas13 fusion to NSUN2 (red) or TET (blue), respectively potentially resulting in a decreased (red arrow, left) or increased (green arrow, right) translation.

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