TY - JOUR
T1 - Fine tuning of globin gene expression by DNA methylation
AU - Goren, Alon
AU - Simchen, Giora
AU - Fibach, Eitan
AU - Szabo, Piroska E.
AU - Tanimoto, Keiji
AU - Chakalova, Lyubomira
AU - Pfeifer, Gerd P.
AU - Fraser, Peter J.
AU - Engel, James D.
AU - Cedar, Howard
PY - 2006/12/20
Y1 - 2006/12/20
N2 - Expression patterns in the globin gene cluster are subject to developmental regulation in vivo. While the γA and γG genes are expressed in fetal liver, both are silenced in adult erythrocytes. In order to decipher the role of DNA methylation in this process, we generated a YAC transgenic mouse system that allowed us to control γA methylation during development. DNA methylation causes a 20-fold repression of γ A both in non-erythroid and adult erythroid cells. In erythroid cells this modification works as a dominant mechanism to repress γ gene expression, probably through changes in histone acetylation that prevent the binding of erythroid transcription factors to the promoter. These studies demonstrate that DNA methylation serves as an elegant in vivo fine-tuning device for selecting appropriate genes in the globin locus. In addition, our findings provide a mechanism for understanding the high levels of γ-globin transcription seen in patients with Hereditary Persistence of Fetal Hemoglobin, and help explain why 5azaC and butyrate compounds stimulate γ-globin expression in patients with β-hemoglobinopathies.
AB - Expression patterns in the globin gene cluster are subject to developmental regulation in vivo. While the γA and γG genes are expressed in fetal liver, both are silenced in adult erythrocytes. In order to decipher the role of DNA methylation in this process, we generated a YAC transgenic mouse system that allowed us to control γA methylation during development. DNA methylation causes a 20-fold repression of γ A both in non-erythroid and adult erythroid cells. In erythroid cells this modification works as a dominant mechanism to repress γ gene expression, probably through changes in histone acetylation that prevent the binding of erythroid transcription factors to the promoter. These studies demonstrate that DNA methylation serves as an elegant in vivo fine-tuning device for selecting appropriate genes in the globin locus. In addition, our findings provide a mechanism for understanding the high levels of γ-globin transcription seen in patients with Hereditary Persistence of Fetal Hemoglobin, and help explain why 5azaC and butyrate compounds stimulate γ-globin expression in patients with β-hemoglobinopathies.
UR - http://www.scopus.com/inward/record.url?scp=44149110031&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0000046
DO - 10.1371/journal.pone.0000046
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C2 - 17183675
AN - SCOPUS:44149110031
SN - 1932-6203
VL - 1
JO - PLoS ONE
JF - PLoS ONE
IS - 1
M1 - e46
ER -