| Autor: |
Chen Z; Center of Excellence in Sickle Cell Disease, Division of Hematology/Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA., Luo HY, Basran RK, Hsu TH, Mang DW, Nuntakarn L, Rosenfield CG, Patrinos GP, Hardison RC, Steinberg MH, Chui DH |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular and cellular biology [Mol Cell Biol] 2008 Jul; Vol. 28 (13), pp. 4386-93. Date of Electronic Publication: 2008 Apr 28. |
| DOI: |
10.1128/MCB.00071-08 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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