Document Detail


Epigenetic modifiers are necessary but not sufficient for reprogramming non-myelinating cells into myelin gene-expressing cells.
MedLine Citation:
PMID:  20885955     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jia Liu; Juan Sandoval; Sung Tae Doh; Li Cai; Gerardo López-Rodas; Patrizia Casaccia
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-27
Journal Detail:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-10-04     Completed Date:  2011-02-18     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e13023     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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:
NS-R01-42925-08/NS/NINDS NIH HHS; NS-R01-42925-08-S1/NS/NINDS NIH HHS; R01 NS042925/NS/NINDS NIH HHS; R21-EY018738/EY/NEI NIH HHS
Chemical
Reg. No./Substance:
0/Chromatin; 0/Histones; 0/Myelin Proteins; 0/Transcription Factors
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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