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

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Title: DNA methylation regulates the expression of the negative transcriptional regulators ID2 and ID4 during OPC differentiation
Authors: Patrick Vandormael, Jos Prickaerts, Niels Hellings, Veerle Somers, Tim Vanmierlo, Daniel L.A. van den Hove, Melissa Schepers, Renzo J. M. Riemens, Ben Rombaut, Assia Tiane
Contributors: Vanmierlo, Tim/0000-0003-2912-0578, TIANE, Assia, SCHEPERS, Melissa, Riemens, Renzo, ROMBAUT, Ben, VANDORMAEL, Patrick, SOMERS, Veerle, Prickaerts, Jos, HELLINGS, Niels, van den Hove, Daniel, VANMIERLO, Tim
Source: Cell Mol Life Sci
Publisher Information: Springer Science and Business Media LLC, 2021.
Publication Year: 2021
Subject Terms: 0301 basic medicine, Biochemistry & Molecular Biology, 3101 Biochemistry and cell biology, PROTEINS, Gene Expression, 0601 Biochemistry and Cell Biology, Methylation, Epigenesis, Genetic, Myelination, Mice, 03 medical and health sciences, Oligodendrocyte precursor cell, 3205 Medical biochemistry and metabolomics, 3211 Oncology and carcinogenesis, Animals, Cells, Cultured, Myelin Sheath, Inhibitor of Differentiation Protein 2, Oligodendrocyte Precursor Cells, Science & Technology, MULTIPLE-SCLEROSIS LESIONS, 1103 Clinical Sciences, Cell Differentiation, Cell Biology, ID2, DNA Methylation, 0606 Physiology, CNS REMYELINATION, Oligodendrocyte, OLIGODENDROCYTES, Gene Expression Regulation, Remyelination, ID4, METHYLTRANSFERASE INHIBITORS, Original Article, Inhibitor of Differentiation Proteins, Life Sciences & Biomedicine, Transcription Factors
Description: 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.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 1420-9071
1420-682X
DOI: 10.1007/s00018-021-03927-2
Access URL: https://link.springer.com/content/pdf/10.1007/s00018-021-03927-2.pdf
https://pubmed.ncbi.nlm.nih.gov/34482420
https://cris.maastrichtuniversity.nl/en/publications/3cd30906-5126-47f4-8a7a-88455931fcfc
https://doi.org/10.1007/s00018-021-03927-2
https://cris.maastrichtuniversity.nl/en/publications/dna-methylation-regulates-the-expression-of-the-negative-transcri
https://link.springer.com/content/pdf/10.1007/s00018-021-03927-2.pdf
https://link.springer.com/article/10.1007/s00018-021-03927-2
https://pubmed.ncbi.nlm.nih.gov/34482420/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558293
http://hdl.handle.net/1942/35758
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) .
Accession Number: edsair.doi.dedup.....7d74c08df771e1f6852077c1d52b5201
Database: OpenAIRE
Description
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.
ISSN:14209071
1420682X
DOI:10.1007/s00018-021-03927-2