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Title: | A Functional element necessary for fetal hemoglobin silencing |
Authors: | Sankaran, V.G. Xu, J. Byron, R. Greisman, H.A. Fisher, C. Weatherall, D.J. Sabath, D.E. Groudine, M. Orkin, S.H. Premawardhena, A. Bender, M.A. |
Keywords: | |
Issue Date: | 2011 |
Publisher: | Massachusetts Medical Society |
Citation: | The New England Journal of Medicine. 2011; 365(9): 807-14 |
Abstract: | BACKGROUND: An improved understanding of the regulation of the fetal hemoglobin genes holds promise for the development of targeted therapeutic approaches for fetal hemoglobin induction in the β-hemoglobinopathies. Although recent studies have uncovered trans-acting factors necessary for this regulation, limited insight has been gained into the cis-regulatory elements involved. METHODS: We identified three families with unusual patterns of hemoglobin expression, suggestive of deletions in the locus of the β-globin gene (β-globin locus). We performed array comparative genomic hybridization to map these deletions and confirmed breakpoints by means of polymerase-chain-reaction assays and DNA sequencing. We compared these deletions, along with previously mapped deletions, and studied the trans-acting factors binding to these sites in the β-globin locus by using chromatin immunoprecipitation. RESULTS: We found a new (δβ)(0)-thalassemia deletion and a rare hereditary persistence of fetal hemoglobin deletion with identical downstream breakpoints. Comparison of the two deletions resulted in the identification of a small intergenic region required for γ-globin (fetal hemoglobin) gene silencing. We mapped a Kurdish β(0)-thalassemia deletion, which retains the required intergenic region, deletes other surrounding sequences, and maintains fetal hemoglobin silencing. By comparing these deletions and other previously mapped deletions, we elucidated a 3.5-kb intergenic region near the 5' end of the δ-globin gene that is necessary for γ-globin silencing. We found that a critical fetal hemoglobin silencing factor, BCL11A, and its partners bind within this region in the chromatin of adult erythroid cells. CONCLUSIONS: By studying three families with unusual deletions in the β-globin locus, we identified an intergenic region near the δ-globin gene that is necessary for fetal hemoglobin silencing. (Funded by the National Institutes of Health and others.). |
Description: | Indexed in MEDLINE |
URI: | http://repository.kln.ac.lk/handle/123456789/2072 |
ISSN: | 0028-4793[Print] 1533-4406 (Electronic) |
Appears in Collections: | Journal/Magazine Articles |
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nejm 2011.pdf | 650.58 kB | Adobe PDF | View/Open |
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