Heterochromatin Protein 1γ Is a Novel Epigenetic Repressor of Human Embryonic ε-Globin Gene Expression

Production of hemoglobin during development is tightly regulated. For example, expression from the human beta-globin gene locus, comprising beta, delta, epsilon, and gamma globin genes, switches from beta-globin to epsilon-globin during embryonic development and then from beta-globin to beta-globin after birth. Expression of human beta-globin in mice has been shown to ameliorate anemia caused by beta-globin mutations, including those causing beta-thalassemia and sickle cell disease, raising the prospect that reactivation of beta-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 beta-globin gene silencing remain elusive. Here we found that the heterochromatin protein HP1 gamma, a multifunctional chromatin-and DNA-binding protein with roles in transcriptional activation and elongation, represses epsilon-globin expression by interacting with a histone-modifying enzyme, lysine methyltransferase SUV4-20h2. Silencing of HP1 gamma 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 epsilon-globin gene and greatly increased epsilon-globin expression. In addition, using chromatin immunoprecipitation, we showed that SUV4-20h2 facilitates the deposition of HP1 gamma on the epsilon-globin-proximal promoter. Thus, these data indicate that HP1 gamma is a novel epigenetic repressor of epsilon-globin gene expression and provide a potential strategy for targeted therapies for beta-thalassemia and sickle cell disease.