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

doi:10.1016/j.celrep.2016.03.060

Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage

Cell Rep. 2016 Apr 26;15(4):748-760. doi: 10.1016/j.celrep.2016.03.060. Epub 2016 Apr 14.

Authors

Sarah Moyon¹, Jimmy L Huynh², Dipankar Dutta³, Fan Zhang¹, Dan Ma⁴, Seungyeul Yoo⁵, Rebecca Lawrence¹, Michael Wegner⁶, Gareth R John⁷, Ben Emery⁸, Catherine Lubetzki⁹, Robin J M Franklin⁴, Guoping Fan¹⁰, Jun Zhu⁵, Jeffrey L Dupree¹¹, Patrizia Casaccia¹²

Affiliations

¹ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
² Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
³ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴ Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AH, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0AH, UK.
⁵ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ Institut für Biochemie, Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany.
⁷ Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁸ Jungers Center for Neurosciences Research and Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.
⁹ Sorbonne Universités UPMC Université, Paris 06, UMR_S 1127, ICM-GHU Pitié-Salpêtrière, 75013 Paris, France.
¹⁰ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹¹ Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
¹² Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: patrizia.casaccia@mssm.edu.

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.

Abstract

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