A T-to-G Transversion at Nucleotide −567 Upstream of HBG2 in a GATA-1 Binding Motif Is Associated with Elevated Hemoglobin F Journal Articles uri icon

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  • Increased fetal hemoglobin (Hb F; alpha(2)gamma(2)) production in adults can ameliorate the clinical severity of sickle cell disease and beta-thalassemia major. Thus, understanding the regulation of gamma-globin gene expression and its silencing in adults has potential therapeutic implications. We studied a father and son in an Iranian-American family who had elevated Hb F levels and found a novel T-to-G transversion at nucleotide (nt) -567 of the HBG2 promoter. This mutation alters a GATA-1 binding motif to a GAGA sequence located within a previously identified silencing element. DNA-protein binding assays showed that the GATA motif of interest is capable of binding GATA-1 transcription factor in vitro and in vivo. Truncation analyses of the HBG2 promoter linked to a luciferase reporter gene revealed a negative regulatory activity present between nt -675 and -526. In addition, the T-to-G mutation at the GATA motif increased the promoter activity by two- to threefold in transiently transfected erythroid cell lines. The binding motif is uniquely conserved in simian primates with a fetal pattern of gamma-globin gene expression. These results suggest that the GATA motif under study has a functional role in silencing gamma-globin gene expression in adults. The T-to-G mutation in this motif disrupts GATA-1 binding and the associated repressor complex, abolishing its silencing effect and resulting in the up-regulation of gamma-globin gene expression in adults.


  • Chen, Zhiyi
  • Luo, Hong-Yuan
  • Basran, Raveen K
  • Hsu, Tien-Huei
  • Mang, Daniel WH
  • Nuntakarn, Lalana
  • Rosenfield, Cathy G
  • Patrinos, George P
  • Hardison, Ross C
  • Steinberg, Martin H
  • Chui, David Hing-kwei

publication date

  • July 1, 2008

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