Stage-specific expression of myelin basic protein in oligodendrocytes involves Nkx2.2-mediated repression that is relieved by the Sp1 transcription factor.
The homeodomain-containing protein Nkx2.2 is critical for the development of oligodendrocyte lineage cells, but the target genes of Nkx2.2 regulation have not been identified. In the present study, we found that the myelin basic protein gene is one of the genes that is regulated by Nkx2.2. Expression of Nkx2.2 represses the expression of myelin basic protein in oligodendrocyte progenitors. Two regulatory elements in the myelin basic protein promoter were identified and found to interact with Nkx2.2 in vitro. Despite their sequence divergence, both sites were involved in the Nkx2.2-mediated repression of the myelin basic protein promoter. Binding of Nkx2.2 also blocked and disrupted the binding of the transcriptional activator Puralpha to the myelin basic protein promoter. Additionally Nkx2.2 recruited a histone deacetylase 1-mSin3A complex to the myelin basic protein promoter. We also found that the transcription factor Sp1 was able to compete off the binding of Nkx2.2 to its consensus binding site in vitro and reversed the repressive effect of Nkx2.2 in vivo. Our data revealed a novel role for Nkx2.2 in preventing the precocious expression of myelin basic protein in immature oligodendrocytes. Based on this study and our previous reports, a model for myelin basic protein gene control is proposed.
Wei
Qiou
Q
Division of Basic Biomedical Sciences, University of South Dakota School of Medicine, Vermillion, South Dakota 57069, USA.
Miskimins
W Keith
WK
Miskimins
Robin
R
D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005786:Gene Expression Regulation / Q000502:physiology*; D006655:Histone Deacetylases / Q000378:metabolism; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D004676:Myelin Basic Protein; C000715628:Nkx2-2 protein, rat; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish; D006655:Histone Deacetylases