The stability of the myelinating oligodendrocyte transcriptome is regulated by the nuclear lamina

Mathilde Pruvost; Julia Patzig; Camila Yattah; Ipek Selcen; Marylens Hernandez; Hye-Jin Park; Sarah Moyon; Shibo Liu; Malia S Morioka; Lindsay Shopland; Osama Al-Dalahmah; Jaroslav Bendl; John F Fullard; Panos Roussos; James Goldman; Ye He; Jeffrey L Dupree; Patrizia Casaccia

doi:10.1016/j.celrep.2023.112848

The stability of the myelinating oligodendrocyte transcriptome is regulated by the nuclear lamina

Cell Rep. 2023 Aug 29;42(8):112848. doi: 10.1016/j.celrep.2023.112848. Epub 2023 Jul 28.

Authors

Mathilde Pruvost¹, Julia Patzig¹, Camila Yattah², Ipek Selcen², Marylens Hernandez³, Hye-Jin Park¹, Sarah Moyon¹, Shibo Liu⁴, Malia S Morioka⁵, Lindsay Shopland⁶, Osama Al-Dalahmah⁷, Jaroslav Bendl⁸, John F Fullard⁸, Panos Roussos⁹, James Goldman⁷, Ye He⁵, Jeffrey L Dupree¹⁰, Patrizia Casaccia¹¹

Affiliations

¹ Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York, 85 St. Nicholas Terrace, New York, NY 10031, USA.
² Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York, 85 St. Nicholas Terrace, New York, NY 10031, USA; Graduate Program in Biochemistry, The Graduate Center of The City University of New York, 365 5(th) Avenue, New York, NY 10016, USA.
³ Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁴ Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York, 85 St. Nicholas Terrace, New York, NY 10031, USA; Structural Biology Initiative, Advanced Science Research Center at the Graduate Center, City University of New York, New York, NY 10031, USA.
⁵ Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York, 85 St. Nicholas Terrace, New York, NY 10031, USA; Macaulay Honors College, City College of New York, New York, NY 10031, USA.
⁶ Jackson Laboratory, 1650 Santa Ana Ave, Sacramento, CA 95835, USA.
⁷ Department of Pathology and Cell Biology, Division of Neuropathology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, and the New York Presbyterian Hospital, New York, NY 10032, USA.
⁸ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, 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.
⁹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, 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; Mental Illness Research, Education, and Clinical Center (VISN 2 South), James J. Peters VA Medical Center, Bronx, NY 10468, USA; Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA.
¹⁰ Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
¹¹ Neuroscience Initiative at the Advanced Science Research Center of the Graduate Center of the City University of New York, 85 St. Nicholas Terrace, New York, NY 10031, USA; Graduate Program in Biochemistry, The Graduate Center of The City University of New York, 365 5(th) Avenue, New York, NY 10016, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate Program in Biology, The Graduate Center of The City University of New York, 365 5th Avenue, New York, NY 10016, USA. Electronic address: pcasaccia@gc.cuny.edu.

Abstract

Oligodendrocytes are specialized cells that insulate and support axons with their myelin membrane, allowing proper brain function. Here, we identify lamin A/C (LMNA/C) as essential for transcriptional and functional stability of myelinating oligodendrocytes. We show that LMNA/C levels increase with differentiation of progenitors and that loss of Lmna in differentiated oligodendrocytes profoundly alters their chromatin accessibility and transcriptional signature. Lmna deletion in myelinating glia is compatible with normal developmental myelination. However, altered chromatin accessibility is detected in fully differentiated oligodendrocytes together with increased expression of progenitor genes and decreased levels of lipid-related transcription factors and inner mitochondrial membrane transcripts. These changes are accompanied by altered brain metabolism, lower levels of myelin-related lipids, and altered mitochondrial structure in oligodendrocytes, thereby resulting in myelin thinning and the development of a progressively worsening motor phenotype. Overall, our data identify LMNA/C as essential for maintaining the transcriptional and functional stability of myelinating oligodendrocytes.

Keywords: CP: Neuroscience; brain; chromatin; epigenetics; myelin; nucleus; progenitors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cells, Cultured
Chromatin / metabolism
Myelin Sheath / metabolism
Nuclear Lamina*
Oligodendroglia / metabolism
Transcriptome* / genetics

Substances

Chromatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding