期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 31, 期 4, 页码 876-883出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00725-10
关键词
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资金
- National Institutes of Health [R01 HL072351, R01 HL073440]
- UAB CMB [T32 GM008111]
- Carmichael Scholarship
- Cooley's Anemia Foundation
- UNICO Foundation Inc.
- Joseph Ruisi
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.
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