Heterochromatin protein 1 γ is a novel epigenetic repressor of human embryonic ε-globin gene expression

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.