title: Human globin knock-in mice complete fetal-to-adult hemoglobin switching in postnatal development.
abstract: Elevated levels of fetal γ-globin can cure disorders caused by mutations in the adult β-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 β-globin locus complete their fetal-to-adult hemoglobin switch prior to birth, with human γ-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 γ-globin is the dominant globin chain produced during mid- to late gestation. Human γ- and β-globin gene competition is evident around the time of birth, and γ-globin chain production diminishes in postnatal life, with transient production of HbF reticulocytes. Following completion of the γ- to-β-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 γ-globin expression in mouse definitive erythroid cells.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: McConnell
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Huo
authors.forename: Shanrun
authors.initials: S
authors.lastname: Liu
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Ryan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000235:genetics; D021901:DNA, Intergenic / Q000235:genetics / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D005812:Genes, Switch; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D011247:Pregnancy; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics* / Q000378:metabolism*; D055545:gamma-Globins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D021901:DNA, Intergenic; D011994:Recombinant Proteins; D055544:beta-Globins; D055545:gamma-Globins; D005319:Fetal Hemoglobin