title: Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage.
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.
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Moyon
authors.affiliation: 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.
authors.forename: Jimmy L
authors.initials: JL
authors.lastname: Huynh
authors.affiliation: Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Dipankar
authors.initials: D
authors.lastname: Dutta
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Dan
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Seungyeul
authors.initials: S
authors.lastname: Yoo
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lawrence
authors.affiliation: Institut für Biochemie, Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054 Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wegner
authors.affiliation: 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.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: John
authors.affiliation: Jungers Center for Neurosciences Research and Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Emery
authors.affiliation: Sorbonne Universités UPMC Université, Paris 06, UMR_S 1127, ICM-GHU Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lubetzki
authors.affiliation: 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.
authors.forename: Robin J M
authors.initials: RJM
authors.lastname: Franklin
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Guoping
authors.initials: G
authors.lastname: Fan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Dupree
authors.affiliation: 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.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casaccia