Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage

Sarah Moyon, Jimmy L. Huynh, Dipankar Dutta, Fan Zhang, Dan Ma, Seungyeul Yoo, Rebecca Lawrence, Michael Wegner, Gareth R. John, Ben Emery, Catherine Lubetzki, Robin J.M. Franklin, Guoping Fan, Jun Zhu, Jeffrey L. Dupree, Patrizia Casaccia

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

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. Moyon et al. combine high-resolution methylomics, RNA sequencing, and analysis of multiple transgenic lines to define a critical role for DNA methylation in developmental myelination. Ablation of Dnmt1 decreases proliferation yet minimally impacts progenitors while impairing the late stages of differentiation, which require alternative splicing.

Original languageEnglish (US)
Pages (from-to)748-760
Number of pages13
JournalCell Reports
Volume15
Issue number4
DOIs
StatePublished - Apr 26 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Moyon, S., Huynh, J. L., Dutta, D., Zhang, F., Ma, D., Yoo, S., Lawrence, R., Wegner, M., John, G. R., Emery, B., Lubetzki, C., Franklin, R. J. M., Fan, G., Zhu, J., Dupree, J. L., & Casaccia, P. (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