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

Abstract

Elevated levels of fetal ␥-globin can cure disorders caused by mutations in the adult ␤-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 ␤-globin locus complete their fetal-to-adult hemoglobin switch prior to birth, with human ␥-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 ␥-globin is the dominant globin chain produced during mid-to late gestation. Human ␥-and ␤-globin gene competition is evident around the time of birth, and ␥-globin chain production diminishes in postnatal life, with transient production of HbF reticulocytes. Following completion of the ␥-to-␤-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 ␥-globin expression in mouse definitive erythroid cells.

PGC-1 Coactivator Activity Is Required for Murine Erythropoiesis

“…By the time of birth, εy-globin transcription has completely ceased (41). In agreement with this observation, neither PGC-1␣ nor PGC-1␤ is still bound to any embryonic or adult globin gene promoters in p0 (definitive) erythroid cells (Fig.…”

“…5). By e14.5, εy-globin is still being expressed, while ␤h1-globin is no longer transcribed (41). Consistent with this expression pattern, PGC-1␣ and PGC-1␤ remain bound to the εy-globin gene promoter but are no longer bound at the ␤h1 promoter (Fig.…”

Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment

“…21 By three months of age, male SS mice showed a lower blood hemoglobin level (9.0 ± 0.31 g/dl, n=6) than AA (11.3 ± 0.1 g/dl, n=5) and AS mice (12.8 ± 0.2 g/dl, n=6). Doppler ultrasound revealed a higher resistive index (RI), but normal mean velocity (MV) and peak systolic velocity (PSV) in the carotid artery in SS than AA and AS mice (n=5–6 for each genotype, Figure 1A).…”

Exploiting genomics and natural genetic variation to decode macrophage enhancers

“…The functional evidence for this flexibility is exemplified by the correct expression of transgenes between species. For example, when the human globin locus is inserted in mouse it is expressed with the same fetal-to-adult switch as it is in humans [65, 66]. …”