Dataset Information

Mi2?-mediated silencing of the fetal ?-globin gene in adult erythroid cells.

ABSTRACT: An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate ?-type globin gene disorders such as sickle cell anemia and ?-thalassemia through activation of the fetal ?-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in ?-globin gene silencing, and Mi2? (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2? relieves ?-globin gene silencing in ?-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, Mi2? binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for ?-globin gene silencing during ?-type globin gene switching. Remarkably, <50% knockdown of Mi2? is sufficient to significantly induce ?-globin gene expression without disrupting erythroid differentiation of primary human CD34(+) progenitors. These results indicate that Mi2? is a potential target for therapeutic induction of fetal hemoglobin.

SUBMITTER: Amaya M

PROVIDER: S-EPMC3637018 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Publications

Mi2β-mediated silencing of the fetal γ-globin gene in adult erythroid cells.

Amaya Maria M Desai Megha M Gnanapragasam Merlin Nithya MN Wang Shou Zhen SZ Zu Zhu Sheng S Williams David C DC Ginder Gordon D GD

Blood 20130226 17

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 indu ...[more]

PMID: 23444401

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Project description:UNLABELLED: BACKGROUND: The ?-globin gene domains of vertebrate animals constitute popular models for studying the regulation of eukaryotic gene transcription. It has previously been shown that in the mouse the developmental switching of globin gene expression correlates with the reconfiguration of an active chromatin hub (ACH), a complex of promoters of transcribed genes with distant regulatory elements. Although it is likely that observations made in the mouse ?-globin gene domain are also relevant for this locus in other species, the validity of this supposition still lacks direct experimental evidence. Here, we have studied the spatial organization of the chicken ?-globin gene domain. This domain is of particular interest because it represents the perfect example of the so-called 'strong' tissue-specific gene domain flanked by insulators, which delimit the area of preferential sensitivity to DNase I in erythroid cells. RESULTS: Using chromosome conformation capture (3C), we have compared the spatial configuration of the ?-globin gene domain in chicken red blood cells (RBCs) expressing embryonic (3-day-old RBCs) and adult (9-day-old RBCs) ?-globin genes. In contrast to observations made in the mouse model, we found that in the chicken, the early embryonic ?-globin gene, ?, did not interact with the locus control region in RBCs of embryonic lineage (3-day RBCs), where this gene is actively transcribed. In contrast to the mouse model, a strong interaction of the promoter of another embryonic ?-globin gene, ?, with the promoter of the adult ?-globin gene, ?A, was observed in RBCs from both 3-day and 9-day chicken embryos. Finally, we have demonstrated that insulators flanking the chicken ?-globin gene domain from the upstream and from the downstream interact with each other, which places the area characterized by lineage-specific sensitivity to DNase I in a separate chromatin loop. CONCLUSIONS: Taken together, our results strongly support the ACH model but show that within a domain of tissue-specific genes, the active status of a promoter does not necessarily correlate with the recruitment of this promoter to the ACH.

Dataset Information

Mi2?-mediated silencing of the fetal ?-globin gene in adult erythroid cells.

Publications

Mi2β-mediated silencing of the fetal γ-globin gene in adult erythroid cells.

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