| Epigenetic modifiers are necessary but not sufficient for reprogramming non-myelinating cells into myelin gene-expressing cells. | |
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MedLine Citation:
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PMID: 20885955 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Modifications on specific histone residues and DNA methylation play an essential role in lineage choice and cellular reprogramming. We have previously shown that histone modifications or combinatorial codes of transcription factors (TFs) are critical for the differentiation of multipotential progenitors into myelinating oligodendrocytes. In this study we asked whether combining global manipulation of DNA methylation and histone acetylation together with the expression of oligodendrocyte-specific TFs, was sufficient to switch the identity of fibroblasts into myelin gene-expressing cells. METHODOLOGY/PRINCIPAL FINDINGS: Transfection of six oligodendrocyte-specific TFs (Olig1, Olig2, Sox10, Mash1, E47 and Nkx2.2) into NIH3T3 fibroblasts was capable of inducing expression of myelin gene promoter-driven reporters, but did not activate endogenous myelin gene expression. These results suggested the existence of a transcriptionally incompetent chromatin conformation in NIH3T3 fibroblasts. Using chromatin immunoprecipitation (ChIP) analysis, we compared the histone code on the conserved regions of myelin genes (i.e. Mbp and Mag) in differentiating oligodendrocyte progenitors and NIH3T3 fibroblasts. Chromatin at myelin gene loci was characterized by the presence of repressive histone modifications (me3K9H3 and me3K27H3) in NIH3T3 fibroblasts and active histone marks (me3K4H3 and AcH3) in oligodendrocyte lineage cells. To induce a transcriptionally competent chromatin signature, NIH3T3 fibroblasts were treated with 5-azadeoxy-citidine (5-AzaC) to decrease DNA methylation, and trichostatin A (TSA) or sirtinol, to favor histone acetylation. Treatment with 5-AzaC/TSA but not sirtinol, resulted in the detection of endogenous myelin gene transcripts in fibroblasts, although not to the levels detected in myelinating cells. Transfection of oligodendrocyte-specific TFs after 5-AzaC/TSA treatment did not further increase myelin gene expression, nor did it reprogram the transcriptional network of NIH3T3 fibroblasts into that of oligodendrocytes. CONCLUSIONS/SIGNIFICANCE: These results suggest that reprogramming of fibroblasts into myelin gene-expressing cells not only requires transcriptional activation, but also chromatin manipulations that go beyond histone acetylation and DNA methylation. |
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Authors:
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Jia Liu; Juan Sandoval; Sung Tae Doh; Li Cai; Gerardo López-Rodas; Patrizia Casaccia |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-09-27 |
Journal Detail:
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Title: PloS one Volume: 5 ISSN: 1932-6203 ISO Abbreviation: PLoS ONE Publication Date: 2010 |
Date Detail:
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Created Date: 2010-10-04 Completed Date: 2011-02-18 Revised Date: 2012-05-22 |
Medline Journal Info:
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Nlm Unique ID: 101285081 Medline TA: PLoS One Country: United States |
Other Details:
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Languages: eng Pagination: e13023 Citation Subset: IM |
Affiliation:
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Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, United States of America. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Animals Cell Differentiation* Cell Line Cell Lineage Cells, Cultured Chromatin / genetics, metabolism DNA Methylation Epigenesis, Genetic* Fibroblasts / cytology*, metabolism Gene Expression* Histones / genetics, metabolism Mice Multipotent Stem Cells / cytology, metabolism Myelin Proteins / genetics*, metabolism NIH 3T3 Cells Oligodendroglia / cytology*, metabolism Rats Transcription Factors / genetics, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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NS-R01-42925-08/NS/NINDS NIH HHS; NS-R01-42925-08-S1/NS/NINDS NIH HHS; R01 NS042925/NS/NINDS NIH HHS; R01 NS042925-08/NS/NINDS NIH HHS; R01 NS042925-08S1/NS/NINDS NIH HHS; R01 NS042925-09/NS/NINDS NIH HHS; R21-EY018738/EY/NEI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chromatin; 0/Histones; 0/Myelin Proteins; 0/Transcription Factors |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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