BCL11A is a major HbF quantitative trait locus in three different populations with β-hemoglobinopathies

Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
Blood Cells Molecules and Diseases (Impact Factor: 2.33). 09/2008; 41(3):255-8. DOI: 10.1016/j.bcmd.2008.06.007
Source: PubMed

ABSTRACT Increased HbF levels or F-cell (HbF containing erythrocyte) numbers can ameliorate the disease severity of beta-thalassemia major and sickle cell anemia. Recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in BCL11A gene on chromosome 2p16.1 were correlated with F-cells among healthy northern Europeans, and HbF among Sardinians with beta-thalassemias. In this study, we showed that SNPs in BCL11A were associated with F-cell numbers in Chinese with beta-thalassemia trait, and with HbF levels in Thais with either beta-thalassemia or HbE trait and in African Americans with sickle cell anemia. Taken together, the data suggest that the functional motifs responsible for modulating F-cells and HbF levels reside within a 3 kb region in the second intron of BCL11A.

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    • "Recent human genetic studies focused on natural variation in the level of HbF expression in human populations shed new light on this complex regulatory process (Thein and Menzel 2009; Thein et al. 2009). More specifically, genome-wide association studies (GWAS) led to the identification of a new HbF-associated locus on chromosome 2, located within the gene BCL11A (Menzel et al. 2007; Thein et al. 2007; Lettre et al. 2008; Sedgewick et al. 2008; So et al. 2008; Uda et al. 2008; Thein and Menzel 2009). Subsequently, the gene BCL11A (also known as Evi9, Ctip1), encoding a zinc finger transcription factor, was shown to function as a regulator of HbF expression (Sankaran et al. 2008). "
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    ABSTRACT: The developmental switch from human fetal (gamma) to adult (beta) hemoglobin represents a clinically important example of developmental gene regulation. The transcription factor BCL11A is a central mediator of gamma-globin silencing and hemoglobin switching. Here we determine chromatin occupancy of BCL11A at the human beta-globin locus and other genomic regions in vivo by high-resolution chromatin immunoprecipitation (ChIP)-chip analysis. BCL11A binds the upstream locus control region (LCR), epsilon-globin, and the intergenic regions between gamma-globin and delta-globin genes. A chromosome conformation capture (3C) assay shows that BCL11A reconfigures the beta-globin cluster by modulating chromosomal loop formation. We also show that BCL11A and the HMG-box-containing transcription factor SOX6 interact physically and functionally during erythroid maturation. BCL11A and SOX6 co-occupy the human beta-globin cluster along with GATA1, and cooperate in silencing gamma-globin transcription in adult human erythroid progenitors. These findings collectively demonstrate that transcriptional silencing of gamma-globin genes by BCL11A involves long-range interactions and cooperation with SOX6. Our findings provide insight into the mechanism of BCL11A action and new clues for the developmental gene regulatory programs that function at the beta-globin locus.
    Genes & development 04/2010; 24(8):783-98. DOI:10.1101/gad.1897310 · 12.64 Impact Factor
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    • "These studies confirmed the effect of the HBS1L - MYB variants and also identified a new set of variants in an intron of the gene BCL11A . Subsequently , these effects were confirmed in populations with sickle cell disease ( Lettre et al , 2008 ) and other populations ( Sedgewick et al , 2008 ) . Additionally , the effect of these HbF - regulating variants on clinical severity has been shown for both sickle cell disease and b - thalassaemia ( Lettre et al , 2008 ; Uda et al , 2008 ; Galanello et al , 2009 ; Nuinoon et al , 2009 ) . "
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    ABSTRACT: The study of haemoglobin switching has represented a focus in haematology due in large part to the clinical relevance of the fetal to adult haemoglobin switch for developing targeted approaches to ameliorate the severity of the beta-haemoglobinopathies. Additionally, the process by which this switch occurs represents an important paradigm for developmental gene regulation. In this review, we provide an overview of both the embryonic primitive to definitive switch in haemoglobin expression, as well as the fetal to adult switch that is unique to humans and old world monkeys. We discuss the nature of these switches and models of their regulation. The factors that have been suggested to regulate this process are then discussed. With the increased understanding and discovery of molecular regulators of haemoglobin switching, such as BCL11A, new avenues of research may lead ultimately to novel therapeutic, mechanism-based approaches to fetal haemoglobin reactivation in patients.
    British Journal of Haematology 03/2010; 149(2):181-94. DOI:10.1111/j.1365-2141.2010.08105.x · 4.96 Impact Factor
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    • "While genetic studies conclude that the Xmn1-HBG2 T allele is the causal variant in some families with HBB-associated hHPFH, the inconsistent association of this SNP with high HbF in some families with HPFH, suggests that the Xmn1-HBG2 SNP requires the presence of intermediary factor(s). Of the three major QTLs, BCL11A correlates most strongly with HbF expression; different SNPs have been implicated in genetic studies, but they all reside within a region of 14 kb in intron 2 of the gene (Fig 4) (Menzel et al, 2007a; Sedgewick et al, 2008; Uda et al, 2008). The BCL11A genotype that is associated with high HbF correlates with reduced BCL11A expression (Sankaran et al, 2008). "
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    ABSTRACT: Sickle cell disease (SCD) and beta thalassaemia, caused by lesions that affect the HBB (beta globin gene), form the most common human genetic disorders world-wide, and represent a major public health problem. Inter-individual variation in foetal haemoglobin (HbF) expression is a known and heritable disease modifier; high HbF levels are correlated with reduced morbidity and mortality in both diseases. This review traces our progress in the understanding of the persistence of HbF in adults as a quantitative trait and the genetic approaches used in teasing out the loci contributing to its variability in normal populations and in patients with haemoglobinopathies. Three major loci -- Xmn1-HBG2 single nucleotide polymorphism, HBS1L-MYB intergenic region on chromosome 6q, and BCL11A -- contribute 20-50% of the trait variance in patients with sickle cell anaemia and healthy European Caucasians. It is likely that the remaining trait variance is due to numerous other loci, many contributing modest effects. Identification of the three major loci has not yet been translated into new therapeutic approaches for HbF reactivation but an immediate application would be an improved prediction of one's ability to produce HbF, which in turn, may improve prediction of disease severity.
    British Journal of Haematology 04/2009; 145(4):455-67. DOI:10.1111/j.1365-2141.2009.07650.x · 4.96 Impact Factor
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