Fine tuning of globin gene expression by DNA methylation

Expression patterns in the globin gene cluster are subject to developmental regulation in vivo. While the gamma(A) and gamma(G) 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...

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Bibliographic Details
Published in:PloS one 2006-12, Vol.1 (1), p.e46-e46
Main Authors: Goren, Alon, Simchen, Giora, Fibach, Eitan, Szabo, Piroska E, Tanimoto, Keiji, Chakalova, Lyubomira, Pfeifer, Gerd P, Fraser, Peter J, Engel, James D, Cedar, Howard
Format: Article
Language:English
Subjects:
Acetylation
Animals
Apoptosis
Artificial chromosomes
Base Sequence
beta-Thalassemia - genetics
Biochemistry
Biology
Cell division
Chromatin
Chromosomes, Artificial, Yeast - genetics
Deoxyribonucleic acid
DNA
DNA binding proteins
DNA damage
DNA Methylation
DNA Primers - genetics
Erythroblasts - metabolism
Erythrocytes
Erythroid cells
Fetal Hemoglobin - genetics
Fetuses
Fibroblasts
gamma-Globins - genetics
Gene Expression
Genes
Genetic engineering
Genetics
Hemoglobin
Hemoglobins
Histones - chemistry
Histones - metabolism
Humans
In vivo methods and tests
Laboratories
Liver
Methylation
Mice
Mice, Transgenic
Molecular Biology/Chromatin Structure
Molecular Biology/DNA Methylation
Molecular Biology/Histone Modification
Patients
Promoter Regions, Genetic
Protein Binding
Proteins
Rodents
Transcription (Genetics)
Transcription factors
Transgenic animals
Transgenic mice
Tuning
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Summary:Expression patterns in the globin gene cluster are subject to developmental regulation in vivo. While the gamma(A) and gamma(G) 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 gamma(A) methylation during development. DNA methylation causes a 20-fold repression of gamma(A) both in non-erythroid and adult erythroid cells. In erythroid cells this modification works as a dominant mechanism to repress gamma 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 gamma-globin transcription seen in patients with Hereditary Persistence of Fetal Hemoglobin, and help explain why 5azaC and butyrate compounds stimulate gamma-globin expression in patients with beta-hemoglobinopathies.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0000046