Heterochromatin Protein 1γ Is a Novel Epigenetic Repressor of Human Embryonic ∊-Globin Genex Expression.

Production of hemoglobin during development is tightly regulated. For example, expression from the human β-globin gene locus, comprising β-, δ-, ∊-, and γ-globin genes, switches from ∊-globin to γ-globin during embryonic development and then from γ-globin to β-globin after birth. Expression of human ∊-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 ∊-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 ∊-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 ∊-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 ∊-globin gene and greatly increased ∊-globin expression. In addition, using chromatin immunoprecipitation, we showed that SUV4-20h2 facilitates the deposition of HP1γ on the ∊-globin-proximal promoter. Thus, these data indicate that HP1γ is a novel epigenetic repressor of ∊-globin gene expression and provide a potential strategy for targeted therapies for β-thalassemia and sickle cell disease. [ABSTRACT FROM AUTHOR]