DNA methylation regulates the expression of the negative transcriptional regulators ID2 and ID4 during OPC differentiation

A. Tiane, M. Schepers, R. Riemens, B. Rombaut, P. Vandormael, V. Somers, J. Prickaerts, N. Hellings, D. van den Hove, T. Vanmierlo*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Web of Science)

Abstract

The differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes is the prerequisite for remyelination in demyelinated disorders such as multiple sclerosis (MS). Epigenetic mechanisms, such as DNA methylation, have been suggested to control the intricate network of transcription factors involved in OPC differentiation. Yet, the exact mechanism remains undisclosed. Here, we are the first to identify the DNA-binding protein inhibitors, Id2 and Id4, as targets of DNA methylation during OPC differentiation. Using state-of-the-art epigenetic editing via CRISPR/dCas9-DNMT3a, we confirm that targeted methylation of Id2/Id4 drives OPC differentiation. Moreover, we show that in the pathological context of MS, methylation and gene expression levels of both ID2 and ID4 are altered compared to control human brain samples. We conclude that DNA methylation is crucial to suppress ID2 and ID4 during OPC differentiation, a process that appears to be dysregulated during MS. Our data do not only reveal new insights into oligodendrocyte biology, but could also lead to a better understanding of CNS myelin disorders.
Original languageEnglish
Pages (from-to)6631-6644
Number of pages14
JournalCellular and Molecular Life Sciences
Volume78
Issue number19-20
Early online date5 Sep 2021
DOIs
Publication statusPublished - Oct 2021

Keywords

  • Oligodendrocyte
  • Oligodendrocyte precursor cell
  • Methylation
  • Myelination
  • ID2
  • ID4
  • MULTIPLE-SCLEROSIS LESIONS
  • CNS REMYELINATION
  • METHYLTRANSFERASE INHIBITORS
  • OLIGODENDROCYTES
  • PROTEINS

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