MBD2 contributes to developmental silencing of the human ?-globin gene.

ABSTRACT: During erythroid development, the embryonic ?-globin gene becomes silenced as erythropoiesis shifts from the yolk sac to the fetal liver where ?-globin gene expression predominates. Previous studies have shown that the ?-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 ?-globin and human fetal ?-globin genes. To determine the roles of MBD2 and DNA methylation in human ?-globin gene silencing, transgenic mice containing all sequences extending from the 5' hypersensitive site 5 (HS5) of the ?-globin locus LCR to the human ?-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 ?-globin transgene expression by 15-20 fold in adult mice. Adult mice containing the entire human ?-globin locus also show an increase in expression of both the ?-globin gene transgene and endogenous ?(Y) and ?(H1) genes in the absence of MBD2. These results indicate that the human ?-globin gene is subject to multilayered silencing mediated in part by MBD2.

SUBMITTER: Rupon JW 

PROVIDER: S-EPMC3062199 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature