Epigenetic regulation of hemoglobin switching in non-human primates

Human hemoglobin switching describes the highly regulated, sequential expression of the 5 β-like globin genes (HBE, HBG2, HBG1, HBD and HBB) of the human β-globin gene complex. The sequential activation of these β or β-like globin genes during human development from early embryonic through late fetal ('adult') stages, and during erythroid maturation, occurs in an order corresponding to their 5' to 3' location on chromosome 11. The β-hemoglobinopathies are the most common inherited diseases in humanity, and are diseases of mutated HBB or its altered regulation. Since the other β-like globin genes can potentially substitute for defective HBB, much translational research is directed toward understanding and manipulating sequential activation at the human β-globin gene complex to treat β-hemoglobinopathies. Non-human primates provide a vital contribution to such efforts because of their recapitulation of the developmental/maturational switch in hemoglobin production as observed in humans (mice do not model this switch). Valuable insights into druggable epigenetic forces that mediate the switch have been thereby gained. We review important lessons learned in non-human primates, complemented by other studies, and suggest rational next steps.