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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2154-2160. Prepublished online as a Blood First Edition Paper on November 9, 2004; DOI 10.1182/blood-2003-11-4069. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-11-4069v1 105/5/2154    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chakalova, L. Articles by Fraser, P. Search for Related Content PubMed PubMed Citation Articles by Chakalova, L. Articles by Fraser, P. Related Collections Red Cells Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS The Corfu thalassemia deletion disrupts -globin gene silencing and reveals post-transcriptional regulation of HbF expression Lyubomira Chakalova, Cameron S. Osborne, Yan-Feng Dai, Beatriz Goyenechea, Anna Metaxotou-Mavromati, Antonios Kattamis, Christos Kattamis, and Peter Fraser From the Laboratory of Chromatin and Gene Expression, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom; and the Thalassemia Unit, 1st Department of Pediatrics, Athens University "Agia Sophia" Children's Hospital, Athens, Greece. The 7.2 kilobase (kb) Corfu thalassemia mutation is the smallest known deletion encompassing a region upstream of the human gene that has been suggested to account for the vastly different phenotypes in hereditary persistence of fetal hemoglobin (HPFH) versus 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 - and -globin gene transcription, steady-state mRNA, and hemoglobin expression levels in primary erythroid cells cultured from several patients with Corfu thalassemia. We show through RNA fluorescence in situ hybridization that the Corfu deletion results in high-level transcription of the fetal genes in cis with a concomitant reduction in transcription of the downstream gene. Surprisingly, we find that elevated gene transcription does not always result in a corresponding accumulation of mRNA or fetal hemoglobin, indicating a post-transcriptional regulation of gene expression. The data suggest that efficient mRNA accumulation and HbF expression are blocked until 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 -globin genes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Beauchemin and M. Trudel Evidence for a Bigenic Chromatin Subdomain in Regulation of the Fetal-to-Adult Hemoglobin Switch Mol. Cell. Biol., March 15, 2009; 29(6): 1635 - 1648. [Abstract] [Full Text] [PDF] R. Mabaera, M. R. Greene, C. A. Richardson, S. J. Conine, C. D. Kozul, and C. H. Lowrey Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin Blood, January 1, 2008; 111(1): 411 - 420. [Abstract] [Full Text] [PDF] J. Dostie, T. A. Richmond, R. A. Arnaout, R. R. Selzer, W. L. Lee, T. A. Honan, E. D. Rubio, A. Krumm, J. Lamb, C. Nusbaum, et al. Chromosome Conformation Capture Carbon Copy (5C): A massively parallel solution for mapping interactions between genomic elements Genome Res., October 1, 2006; 16(10): 1299 - 1309. [Abstract] [Full Text] [PDF] A. Bank Regulation of human fetal hemoglobin: new players, new complexities Blood, January 15, 2006; 107(2): 435 - 443. [Abstract] [Full Text] [PDF] D. Haussecker and N. J. Proudfoot Dicer-Dependent Turnover of Intergenic Transcripts from the Human {beta}-Globin Gene Cluster Mol. Cell. Biol., November 1, 2005; 25(21): 9724 - 9733. [Abstract] [Full Text] [PDF]

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