MBD2 contributes to developmental silencing of the human ε-globin gene.
Blood Cells Mol Dis
; 46(3): 212-9, 2011 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-21296012
ABSTRACT
During erythroid development, the embryonic ε-globin gene becomes silenced as erythropoiesis shifts from the yolk sac to the fetal liver where γ-globin gene expression predominates. Previous studies have shown that the ε-globin gene is autonomously silenced through promoter proximal cis-acting sequences in adult erythroid cells. We have shown a role for the methylcytosine binding domain protein 2 (MBD2) in the developmental silencing of the avian embryonic ρ-globin and human fetal γ-globin genes. To determine the roles of MBD2 and DNA methylation in human ε-globin gene silencing, transgenic mice containing all sequences extending from the 5' hypersensitive site 5 (HS5) of the ß-globin locus LCR to the human γ-globin gene promoter were generated. These mice show correct developmental expression and autonomous silencing of the transgene. Either the absence of MBD2 or treatment with the DNA methyltransferase inhibitor 5-azacytidine increases ε-globin transgene expression by 15-20 fold in adult mice. Adult mice containing the entire human ß-globin locus also show an increase in expression of both the ε-globin gene transgene and endogenous ε(Y) and ß(H1) genes in the absence of MBD2. These results indicate that the human ε-globin gene is subject to multilayered silencing mediated in part by MBD2.
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Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica no Desenvolvimento
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Inativação Gênica
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Proteínas de Ligação a DNA
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Globinas épsilon
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article