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 journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)748-760
JournalCell Reports
Issue number4
Publication statusPublished - 14 Apr 2016

Bibliographical note

2016 The Authors This is an open access article under the CC BY-NC-ND license (

Funding: 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.).


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