Abstract
An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate β-type globin gene disorders such as sickle cell anemia and β-thalassemia through activation of the fetal γ-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in γ-globin gene silencing, and Mi2β (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2β relieves γ-globin gene silencing in β-YAC transgenic murine chemical inducer of dimerization hematopoietic cells and in CD34(+) progenitor-derived human primary adult erythroid cells. We show that independent of MBD2-NuRD and GATA-1/FOG-1/NuRD, Mi2β binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for γ-globin gene silencing during β-type globin gene switching. Remarkably, <50% knockdown of Mi2β is sufficient to significantly induce γ-globin gene expression without disrupting erythroid differentiation of primary human CD34(+) progenitors. These results indicate that Mi2β is a potential target for therapeutic induction of fetal hemoglobin.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adult
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Animals
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Autoantigens / genetics
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Autoantigens / metabolism*
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Carrier Proteins / metabolism
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Cell Differentiation
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Cells, Cultured
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Chromatin Immunoprecipitation
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Erythroid Cells / cytology
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Erythroid Cells / metabolism*
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Fetal Hemoglobin / antagonists & inhibitors
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Fetal Hemoglobin / genetics*
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Fetal Hemoglobin / metabolism
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Gene Expression Regulation*
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Gene Silencing*
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / metabolism*
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Humans
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Kruppel-Like Transcription Factors / metabolism
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Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
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Mi-2 Nucleosome Remodeling and Deacetylase Complex / metabolism*
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Mice
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Mice, Transgenic
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Nuclear Proteins / metabolism
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RNA, Small Interfering / genetics
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Repressor Proteins
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gamma-Globins / antagonists & inhibitors
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gamma-Globins / genetics*
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gamma-Globins / metabolism
Substances
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Autoantigens
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BCL11A protein, human
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CHD4 protein, human
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Carrier Proteins
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Kruppel-Like Transcription Factors
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Nuclear Proteins
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RNA, Small Interfering
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Repressor Proteins
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erythroid Kruppel-like factor
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gamma-Globins
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Fetal Hemoglobin
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Mi-2 Nucleosome Remodeling and Deacetylase Complex