Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A

Vijay G. Sankaran, Tobias F. Menne, Jian Xu, Thomas E. Akie, Guillaume Lettre, Ben Van Handel, Hanna K A Mikkola, Joel N. Hirschhorn, Alan B. Cantor, Stuart H. Orkin

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Abstract

Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the β-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here, we examine BCL11A as a potential regulator of HbF expression. The high-HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the β-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in β-hemoglobin disorders.

Original languageEnglish (US)
Pages (from-to)1839-1842
Number of pages4
JournalScience
Volume322
Issue number5909
DOIs
StatePublished - Dec 19 2008

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Fetal Hemoglobin
Erythroid Cells
Globins
Thalassemia
Genetic Association Studies
Sickle Cell Anemia
Multigene Family
Genes
Hemoglobins
Down-Regulation
Genotype
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Sankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., ... Orkin, S. H. (2008). Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. Science, 322(5909), 1839-1842. https://doi.org/10.1126/science.1165409

Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. / Sankaran, Vijay G.; Menne, Tobias F.; Xu, Jian; Akie, Thomas E.; Lettre, Guillaume; Van Handel, Ben; Mikkola, Hanna K A; Hirschhorn, Joel N.; Cantor, Alan B.; Orkin, Stuart H.

In: Science, Vol. 322, No. 5909, 19.12.2008, p. 1839-1842.

Research output: Contribution to journalArticle

Sankaran, VG, Menne, TF, Xu, J, Akie, TE, Lettre, G, Van Handel, B, Mikkola, HKA, Hirschhorn, JN, Cantor, AB & Orkin, SH 2008, 'Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A', Science, vol. 322, no. 5909, pp. 1839-1842. https://doi.org/10.1126/science.1165409
Sankaran, Vijay G. ; Menne, Tobias F. ; Xu, Jian ; Akie, Thomas E. ; Lettre, Guillaume ; Van Handel, Ben ; Mikkola, Hanna K A ; Hirschhorn, Joel N. ; Cantor, Alan B. ; Orkin, Stuart H. / Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A. In: Science. 2008 ; Vol. 322, No. 5909. pp. 1839-1842.
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abstract = "Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the β-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here, we examine BCL11A as a potential regulator of HbF expression. The high-HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the β-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in β-hemoglobin disorders.",
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