Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage
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Moyon, S., Huynh, J., Dutta, D., Zhang, F., Ma, D., Yoo, S., Lawrence, R., et al. (2016). Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage. Cell Reports, 15 (4), 748-760. https://doi.org/10.1016/j.celrep.2016.03.060
Oligodendrocytes derive from progenitors (OPCs) through the interplay of epigenomic and transcriptional events. By integrating high-resolution methylomics, RNA-sequencing, and multiple transgenic lines, this study defines the role of DNMT1 in developmental myelination. We detected hypermethylation of genes related to cell cycle and neurogenesis during differentiation of OPCs, yet genetic ablation of Dnmt1 resulted in inefficient OPC expansion and severe hypomyelination associated with ataxia and tremors in mice. This phenotype was not caused by lineage switch or massive apoptosis but was characterized by a profound defect of differentiation associated with changes in exon-skipping and intron-retention splicing events and by the activation of an endoplasmic reticulum stress response. Therefore, loss of Dnmt1 in OPCs is not sufficient to induce a lineage switch but acts as an important determinant of the coordination between RNA splicing and protein synthesis necessary for myelin formation.
This work was supported by NIH-NINDS grants R37NS042925 and NS-R0152738 (P.C.) and F31NS077504 (J.L.H.), the UK Multiple Sclerosis Society (R.J.M.F.), and NIH-NIMH grant R01MH090948 (J.Z.).
External DOI: https://doi.org/10.1016/j.celrep.2016.03.060
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267140
Attribution-NonCommercial-NoDerivatives 4.0 International, Attribution-NonCommercial-NoDerivatives 4.0 International, Attribution-NonCommercial-NoDerivatives 4.0 International
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