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Heterochromatin Protein 1γ Is a Novel Epigenetic Repressor of Human Embryonic ɛ-Globin Gene Expression
- Source :
- Journal of Biological Chemistry. 292:4811-4817
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Production of hemoglobin during development is tightly regulated. For example, expression from the human β-globin gene locus, comprising β-, δ-, ϵ-, and γ-globin genes, switches from ϵ-globin to γ-globin during embryonic development and then from γ-globin to β-globin after birth. Expression of human ϵ-globin in mice has been shown to ameliorate anemia caused by β-globin mutations, including those causing β-thalassemia and sickle cell disease, raising the prospect that reactivation of ϵ-globin expression could be used in managing these conditions in humans. Although the human globin genes are known to be regulated by a variety of multiprotein complexes containing enzymes that catalyze epigenetic modifications, the exact mechanisms controlling ϵ-globin gene silencing remain elusive. Here we found that the heterochromatin protein HP1γ, a multifunctional chromatin- and DNA-binding protein with roles in transcriptional activation and elongation, represses ϵ-globin expression by interacting with a histone-modifying enzyme, lysine methyltransferase SUV4–20h2. Silencing of HP1γ expression markedly decreased repressive histone marks and the multimethylation of histone H3 lysine 9 and H4 lysine 20, leading to a significant decrease in DNA methylation at the proximal promoter of the ϵ-globin gene and greatly increased ϵ-globin expression. In addition, using chromatin immunoprecipitation, we showed that SUV4–20h2 facilitates the deposition of HP1γ on the ϵ-globin-proximal promoter. Thus, these data indicate that HP1γ is a novel epigenetic repressor of ϵ-globin gene expression and provide a potential strategy for targeted therapies for β-thalassemia and sickle cell disease.
- Subjects :
- Transcriptional Activation
0301 basic medicine
Chromosomal Proteins, Non-Histone
Heterochromatin
epsilon-Globins
Epigenetic Repression
Biology
Biochemistry
Cell Line
03 medical and health sciences
Epigenetics of physical exercise
hemic and lymphatic diseases
Histone methylation
Humans
Gene Regulation
Epigenetics
Promoter Regions, Genetic
Molecular Biology
Epigenomics
Regulation of gene expression
Histone-Lysine N-Methyltransferase
Cell Biology
DNA Methylation
Molecular biology
Chromatin
030104 developmental biology
Chromobox Protein Homolog 5
DNA methylation
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 292
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....d94f3549830f07b521ccb367ed0a7388