The Corfu δβ thalassemia deletion disrupts γ-globin gene silencing and reveals post-transcriptional regulation of HbF expression
| Autor: | Cameron S. Osborne, A. Metaxotou-Mavromati, Peter Fraser, Yan-Feng Dai, Lyubomira Chakalova, Christos Kattamis, Antonios Kattamis, Beatriz Goyenechea |
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| Rok vydání: | 2005 |
| Předmět: |
Genotype
Transcription Genetic Hereditary persistence of fetal hemoglobin Immunology Biology Biochemistry Transcription (biology) hemic and lymphatic diseases Fetal hemoglobin Gene expression medicine Humans Gene silencing Gene Silencing RNA Messenger Globin Gene Post-transcriptional regulation Cells Cultured Fetal Hemoglobin Sequence Deletion beta-Thalassemia Gene Expression Regulation Developmental Cell Biology Hematology medicine.disease Molecular biology Globins Case-Control Studies |
| Zdroj: | Blood. 105:2154-2160 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2003-11-4069 |
| Popis: | The 7.2 kilobase (kb) Corfu δβ thalassemia mutation is the smallest known deletion encompassing a region upstream of the human δ gene that has been suggested to account for the vastly different phenotypes in hereditary persistence of fetal hemoglobin (HPFH) versus β thalassemia. Fetal hemoglobin (HbF) expression in Corfu heterozygotes and homozygotes is paradoxically dissimilar, suggesting conflicting theories as to the function of the region on globin gene regulation. Here, we measure γ- and β-globin gene transcription, steady-state mRNA, and hemoglobin expression levels in primary erythroid cells cultured from several patients with Corfu δβ thalassemia. We show through RNA fluorescence in situ hybridization that the Corfu deletion results in high-level transcription of the fetal γ genes in cis with a concomitant reduction in transcription of the downstream β gene. Surprisingly, we find that elevated γ gene transcription does not always result in a corresponding accumulation of γ mRNA or fetal hemoglobin, indicating a post-transcriptional regulation of γ gene expression. The data suggest that efficient γ mRNA accumulation and HbF expression are blocked until β mRNA levels fall below a critical threshold. These results explain the Corfu paradox and show that the deleted region harbors a critical element that functions in the developmentally regulated transcription of the β-globin genes. |
| Databáze: | OpenAIRE |
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