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

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

Aston Medical School

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	748-760
Journal	Cell Reports
Volume	15
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2016.03.060
Publication status	Published - 14 Apr 2016

Bibliographical note

2016 The Authors This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Funding: NIH-NINDS grants R37NS042925 and NS-R0152738 (P.C.) and F31NS077504 (J.L.H.), the UK Multiple Sclerosis Society (R.J.M.F.), and NIH-NIMH grant R01MH090948 (J.Z.).

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10.1016/j.celrep.2016.03.060

Functional Characterization of DNA Methylation in
2016 The Authors This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Final published version, 5.95 MBLicence: CC BY-NC-ND 3.0

http://linkinghub.elsevier.com/retrieve/pii/S221112471630331X

Cite this

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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.",

author = "Sarah Moyon and Jimmy l. Huynh and Dipankar Dutta and Fan Zhang and Dan Ma and Seungyeul Yoo and Rebecca Lawrence and Michael Wegner and Gareth r. John and Ben Emery and Catherine Lubetzki and Robin j.m. Franklin and Guoping Fan and Jun Zhu and Jeffrey l. Dupree and Patrizia Casaccia",

note = "2016 The Authors This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Funding: NIH-NINDS grants R37NS042925 and NS-R0152738 (P.C.) and F31NS077504 (J.L.H.), the UK Multiple Sclerosis Society (R.J.M.F.), and NIH-NIMH grant R01MH090948 (J.Z.).",

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AU - Moyon, Sarah

AU - Huynh, Jimmy l.

AU - Dutta, Dipankar

AU - Zhang, Fan

AU - Ma, Dan

AU - Yoo, Seungyeul

AU - Lawrence, Rebecca

AU - Wegner, Michael

AU - John, Gareth r.

AU - Emery, Ben

AU - Lubetzki, Catherine

AU - Franklin, Robin j.m.

AU - Fan, Guoping

AU - Zhu, Jun

AU - Dupree, Jeffrey l.

AU - Casaccia, Patrizia

N1 - 2016 The Authors This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Funding: NIH-NINDS grants R37NS042925 and NS-R0152738 (P.C.) and F31NS077504 (J.L.H.), the UK Multiple Sclerosis Society (R.J.M.F.), and NIH-NIMH grant R01MH090948 (J.Z.).

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N2 - 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.

AB - 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.

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JO - Cell Reports

JF - Cell Reports

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Functional Characterization of DNA Methylation in the Oligodendrocyte Lineage

Abstract

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