m6A mRNA Methylation Is Essential for Oligodendrocyte Maturation and CNS Myelination

Abstract

The molecular mechanisms that govern the maturation of oligodendrocyte lineage cells remain unclear. Emerging studies have shown that N 6 -methyladenosine (m 6 A), the most common internal RNA modification of mammalian mRNA, plays a critical role in various developmental processes. Here, we demonstrate that oligodendrocyte lineage progression is accompanied by dynamic changes in m 6 A modification on numerous transcripts. In vivo conditional inactivation of an essential m 6 A writer component, METTL14, results in decreased oligodendrocyte numbers and CNS hypomyelination, although oligodendrocyte precursor cell (OPC) numbers are normal. In vitro Mettl14 ablation disrupts postmitotic oligodendrocyte maturation and has distinct effects on OPC and oligodendrocyte transcriptomes. Moreover, the loss of Mettl14 in oligodendrocyte lineage cells causes aberrant splicing of myriad RNA transcripts, including those that encode the essential paranodal component neurofascin 155 (NF155). Together, our findings indicate that dynamic RNA methylation plays an important regulatory role in oligodendrocyte development and CNS myelination.

Epitranscriptomic regulation by m6A RNA methylation in brain development and diseases

“…42 Moreover, ablation of the m 6 A writer METTL14 in oligodendrocyte lineage cells led to hypomethylation of several transcription factors ( Hey1 , Klf19 , and Zeb2) , histone modifiers ( Hdac3 , Kdm2b , and Prdm2 ), and growth factors ( Igf-1 , Fgf , and Bmp ) that promote oligodendrocyte maturation and hence reduced the number of mature oligodendrocytes and caused hypomyelination. 83 METTL14 deficiency also resulted in decreased oligodendrocytes-specific neurofascin ( Nfasc ) splice isoform, subsequently producing an aberrant node of Ranvier morphology. 83 Furthermore, METTL14- and YTHDF2-deficient NSCs failed to differentiate to astrocytes.…”

“…83 METTL14 deficiency also resulted in decreased oligodendrocytes-specific neurofascin ( Nfasc ) splice isoform, subsequently producing an aberrant node of Ranvier morphology. 83 Furthermore, METTL14- and YTHDF2-deficient NSCs failed to differentiate to astrocytes. 16 , 79 Collectively, these studies show that m 6 A promotes the maturation of glial cells.…”

m 6 A RNA methylation: from mechanisms to therapeutic potential

“…Genetic knockout of either Mettl3 or Mettl14 is developmentally lethal in mice, with embryos failing to thrive at around E5.5 (Batista et al , 2014; Geula et al , 2015). Analysis of tissue‐specific knockout mouse models of Mettl3 and Mettl14 has revealed essential roles for m 6 A in brain development and function, cardiac homeostasis, immune system development and function, spermatogenesis, and skeletal function (Lin et al , 2017; Yoon et al , 2017; Li et al , 2017a; Rubio et al , 2018; Wang et al , 2018a, 2018c, 2019; Wu et al , 2018b; Dorn et al , 2019; Winkler et al , 2019; Xu et al , 2020). Moreover, knockout of either Mettl3 or Mettl14 severely blocks or delays differentiation in numerous stem cell or progenitor cell systems, including embryonic stem cells, embryonic neuronal stem cells (Yoon et al , 2017; Wang et al , 2018c), hematopoietic stem cells (Vu et al , 2017; Zhang et al , 2017a; Weng et al , 2018a; Cheng et al , 2019; Lee et al , 2019), naïve T cells (Li et al , 2017a), and bone marrow mesenchymal stem cells (Wu et al , 2018b).…”

Oligodendroglial Epigenetics, from Lineage Specification to Activity-Dependent Myelination

“…Recent models using the ablation of Dicer (required for the generation of functional microRNA) or the de novo analysis of oligodendroglial transcriptomic datasets identified microRNAs and lncRNAs that are essential for OPC differentiation. For example, miR-219 , miR-338 , miR-23 , and miR-32 , as well as lnc-OL1 , lnc-158 , and Neat1 , promote differentiation, while miR-27a , miR-212 , and miR-125-3p inhibit differentiation [ 109 , 111 , 141 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 171 , 172 , 173 , 174 ]. Interestingly, these post-transcriptional signals directly regulate some chromatin-modifying genes, suggesting feedback from miRNA and lncRNA regarding chromatin conformation.…”