Human Globin Knock-in Mice Complete Fetal-to-Adult Hemoglobin Switching in Postnatal Development

Elevated levels of fetal gamma-globin can cure disorders caused by mutations in the adult beta-globin gene. This clinical finding has motivated studies to improve our understanding of hemoglobin switching. Unlike humans, mice do not express a distinct fetal globin. Transgenic mice that contain the human beta-globin locus complete their fetal-to-adult hemoglobin switch prior to birth, with human gamma-globin predominantly restricted to primitive erythroid cells. We established humanized (100% human hemoglobin) knock-in mice that demonstrate a distinct fetal hemoglobin (HbF) stage, where gamma-globin is the dominant globin chain produced during mid- to late gestation. Human gamma- and beta-globin gene competition is evident around the time of birth, and gamma-globin chain production diminishes in postnatal life, with transient production of HbF reticulocytes. Following completion of the gamma- to-beta-globin switch, adult erythroid cells synthesize low levels of HbF. We conclude that the knock-in globin genes are expressed in a pattern strikingly similar to that in human development, most notably with postnatal resolution of the fetal-to-adult hemoglobin switch. Our findings are consistent with the importance of BCL11A in hemoglobin switching, since removal of intergenic binding sites for BCL11A results in human gamma-globin expression in mouse definitive erythroid cells.