Fetal hemoglobin silencing in humans

O'Neal, Patricia; Gantt, Nicole M.; Schwartz, Joseph D.; Bhanu, Natarajan V.; Lee, Y. Terry; Moroney, John W.; Reed, Christopher H.; Schechter, Alan N.; Luban, Naomi L.C.; Miller, Jeffery L.

doi:10.1182/blood-2006-04-015859

Cited by 40 publications

(48 citation statements)

References 31 publications

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“…There is a single human ␥-to-␤-globin switch in definitive erythroid cells that is completed after birth. Newborn hemolysates showed HbF levels of 42%, similar to the low end of the range of HbF reported for human infants (32). There is a gradual decline in HbF levels until the steady-state level of 1% is reached by about 3 weeks of age.…”

Section: Humanized ␥␤supporting

confidence: 51%

“…Humans are born with high levels of fetal hemoglobin (HbF) in their red blood cells (RBCs) and complete the switch to adult hemoglobin (HbA) during the first year of life (32,43). Patients with mutations in their adult ␤-globin genes that cause thalassemia or hemoglobinopathies like sickle cell anemia are clinically normal at birth but become progressively anemic upon completion of their fetal-to-adult hemoglobin switch.…”

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confidence: 99%

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

McConnell

Huo

Liu

et al. 2011

Molecular and Cellular Biology

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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.

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Section: Humanized ␥␤supporting

confidence: 51%

mentioning

confidence: 99%

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

McConnell

Huo

Liu

et al. 2011

Molecular and Cellular Biology

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Section: Introductionmentioning

confidence: 99%

“…19,22 Shortly after birth, a switch between fetal and adult globins allows the expression of ␦-and ␤-globin genes, and the decrease of ␥-globin gene expression. 21,23,24 Adult erythropoiesis recapitulates fetal-to-adult hemoglobin switching in the so-called "compressed switch." [25][26][27] Fetal-to-adult switch needs interaction of transcription factors and chromatin remodeling proteins with the locus control region (LCR).…”

Section: Introductionmentioning

confidence: 99%

“…19,22 Shortly after birth, a switch between fetal and adult globins allows the expression of ␦-and ␤-globin genes, and the decrease of ␥-globin gene expression. 21,23,24 Adult The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734.…”

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confidence: 99%

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The role of Ikaros in human erythroid differentiation

Dijon

Bardin

Murati

et al. 2008

Blood

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Ikaros-a factor that positively or negatively controls gene transcription-is active in murine adult erythroid cells, and involved in fetal to adult globin switching. Mice with Ikaros mutations have defects in erythropoiesis and anemia. In this paper, we have studied the role of Ikaros in human erythroid development for the first time. Using a gene-transfer strategy, we expressed Ikaros 6 (Ik6)-a known dominant-negative protein that interferes with normal Ikaros activity-in cord blood or apheresis CD34 ؉ cells that were induced to differentiate along the erythroid pathway. Lentivirally induced Ik6-forced expression resulted in increased cell death, decreased cell proliferation, and decreased expression of erythroid-specific genes, including GATA1 and fetal and adult globins. In contrast, we observed the maintenance of a residual myeloid population that can be detected in this culture system, with a relative increase of myeloid gene expression, including PU1. IntroductionThe transcription factor Ikaros (also known as LyF-1) was first described to interact with Cd3␦ and TdT promoters in murine thymocyte cells. 1,2 Its sequence is highly conserved between mice and humans, [3][4][5] and its expression is high in the developing and adult hematopoietic systems. 1,6 Ikaros proteins are characterized by the presence of 2 Krüppel-like zinc finger domains. The N-terminal domain is involved in DNA binding, 2,7 while the C-terminal domain is required for homo-or heterodimerization with family members and is composed of 2 zinc fingers. 8 The Ikaros gene contains 7 translated exons and encodes 9 isoforms by means of alternative splicing that alters expression of exons 3 to 6. 2,7 In these different proteins, the number of N-terminal zinc fingers varies from 0 to 4; this combination determines DNA binding affinity. At least 3 zinc fingers in this domain are necessary to efficiently bind to DNA. Ik1, Ik2, Ik3, and IKX are considered as functional isoforms. However, Ik4 can only bind DNA on palindromic sequences. 7 Ik5, Ik6, Ik7, and Ik8 are considered dominantnegative (DN) isoforms because of their capacity to bind other isoforms and their inefficiency to bind DNA. 8 Gene-targeting studies evidenced the fundamental role of Ikaros in hematopoiesis, in particular in T and B lymphocytes, natural killer (NK) and dendritic cells, and stem cells. [9][10][11][12] In addition, analysis of Ikaros L/L mice (insertion of the ␤-Gal gene in exon-2 of the Ikaros gene) revealed that Ikaros is expressed at low levels in a majority of Ter-119 ϩ erythroid cells. 10 Other studies of Ikaros DN (deletion of exon 7) and null (deletion of dimerization domain) mice show that Ikaros is important for erythroid differentiation. 13 These mice display a decrease of erythroid precursor numbers, and a drop in hematocrit levels 2 to 3 weeks after birth. In MEL (murine erythroleukemia) cells, Ikaros is associated with the chromatin remodelling PYR complex which binds to an intergenic domain between the ␥-globin and ␤-globin genes, and facilitates the switch be...

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Induction of foetal haemoglobin synthesis in erythroid progenitor stem cells: mediated by water‐soluble components of Terminalia catappa

Aimola

Inuwa

Nok

et al. 2014

Cell Biochemistry & Function

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Current novel therapeutic agents for the treatment of sickle cell anaemia (SCA) focus on increasing foetal haemoglobin (HbF) levels in SCA patients. Unfortunately, the only approved HbF-inducing agent, hydroxyurea, has long-term unpredictable side effects. Studies have shown the potential of plant compounds to modulate HbF synthesis in primary erythroid progenitor stem cells. We isolated a novel HbF-inducing Terminalia catappa distilled water active fraction (TCDWF) from Terminalia catappa leaves that induced the commitment of erythroid progenitor stem cells to the erythroid lineage and relatively higher HbF synthesis of 9.2- and 6.8-fold increases in both erythropoietin (EPO)-independent and EPO-dependent progenitor stem cells respectively. TCDWF was differentially cytotoxic to EPO-dependent and EPO-independent erythroid progenitor stem cell cultures as revealed by lactate dehydrogenase release from the cells. TCDWF demonstrated a protective effect on EPO-dependent and not EPO-independent progenitor cells. TCDWF induced a modest increase in caspase 3 activity in EPO-independent erythroid progenitor stem cell cultures compared with a significantly higher (P˂0.05) caspase 3 activity in EPO-dependent ones. The results demonstrate that TCDWF may hold promising HbF-inducing compounds, which work synergistically, and suggest a dual modulatory effect on erythropoiesis inherent in this active fraction.

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Fetal hemoglobin silencing in humans

Cited by 40 publications

References 31 publications

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

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

The role of Ikaros in human erythroid differentiation

Induction of foetal haemoglobin synthesis in erythroid progenitor stem cells: mediated by water‐soluble components of Terminalia catappa

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