During the differentiation of an erythrocyte, the developing erythroblast shuts down expression of most of its genes but preserves high levels of expression of certain key genes, such as those encoding hemoglobin and critical membrane proteins. In this issue of the JCI, Gallagher et al. show that a specialized type of DNA sequence element known as an insulator protects the expression of ankyrin, a key membrane protein. In several kindreds, mutations in the insulator led to impaired ankyrin expression and congenital hemolytic anemia. This work provides important insights into ways in which epigenetic changes can alter gene expression and thereby lead to human disease.