Sedgewick, A. E., Timofeev, N., Sebastiani, P., So, J. C. C., Ma, E.S.K., Chan, L. C. et al. BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood Cells Mol. Dis. 41, 255-258
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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- "The contribution of the QTL on chromosome 6q23 to the genetic variance of haemoglobin F/F-cells is estimated to be 19 per cent, and the contribution of BCL11A to be 15 per cent41–43. Sedgewick et al49 reported that SNPs in BCL11A are associated with foetal haemoglobin production in Thais with either β-thalassaemia or Hb E trait (as well as in African Americans with sickle cell anaemia), and with F-cell numbers in Chinese individuals with β-thalassaemia trait. These limited studies suggest that BCL11a polymorphisms may be important modulators of foetal haemoglobin in HbE/β-thalassaemia. "
ABSTRACT: Haemoglobin E-beta thalassaemia (Hb E/β-thalassaemia) is the genotype responsible for approximately one-half of all severe beta-thalassaemia worldwide. The disorder is characterized by marked clinical variability, ranging from a mild and asymptomatic anaemia to a life-threatening disorder requiring transfusions from infancy. The phenotypic variability of Hb E/β-thalassaemia and the paucity of long-term clinical data, present challenges in providing definitive recommendations for the optimal management of patients. Genetic factors influencing the severity of this disorder include the type of beta-thalassaemia mutation, the co-inheritance of alpha-thalassaemia, and polymorphisms associated with increased production of foetal haemoglobin. Other factors, including a variable increase in serum erythropoietin in response to anaemia, previous or ongoing infection with malaria, previous splenectomy and other environmental influences, may be involved. The remarkable variation, and the instability, of the clinical phenotype of Hb E beta-thalassaemia suggests that careful tailoring of treatment is required for each patient, and that therapeutic approaches should be re-assessed over-time.The Indian Journal of Medical Research 10/2011; 134(4):522-31. · 1.66 Impact Factor
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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). "
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 ) . "
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