A T-to-G transversion at nucleotide -567 upstream of HBG2 in a GATA-1 binding motif is associated with elevated hemoglobin F

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

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Increased fetal hemoglobin (Hb F; α2γ2) production in adults can ameliorate the clinical severity of sickle cell disease and β-thalassemia major. Thus, understanding the regulation of γ-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 γ-globin gene expression. These results suggest that the GATA motif under study has a functional role in silencing γ-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 γ-globin gene expression in adults.

Original languageEnglish (US)
Pages (from-to)4386-4393
Number of pages8
JournalMolecular and cellular biology
Volume28
Issue number13
DOIs
StatePublished - Jul 2008

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'A T-to-G transversion at nucleotide -567 upstream of HBG2 in a GATA-1 binding motif is associated with elevated hemoglobin F'. Together they form a unique fingerprint.

  • Cite this

    Chen, Z., Luo, H. Y., Basran, R. K., Hsu, T. H., Mang, D. W. H., Nuntakarn, L., Rosenfield, C. G., Patrinos, G. P., Hardison, R. C., Steinberg, M. H., & Chui, D. H. K. (2008). A T-to-G transversion at nucleotide -567 upstream of HBG2 in a GATA-1 binding motif is associated with elevated hemoglobin F. Molecular and cellular biology, 28(13), 4386-4393. https://doi.org/10.1128/MCB.00071-08