A Functional Element Necessary for Fetal Hemoglobin Silencing
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- 1 September 2011
- journal article
- research article
- Published by Massachusetts Medical Society in The New England Journal of Medicine
- Vol. 365 (9), 807-814
- https://doi.org/10.1056/nejmoa1103070
Abstract
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. 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. 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 β0-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. 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.)Keywords
This publication has 30 references indexed in Scilit:
- Update on fetal hemoglobin gene regulation in hemoglobinopathiesCurrent Opinion in Pediatrics, 2011
- A Dominant Mutation in the Gene Encoding the Erythroid Transcription Factor KLF1 Causes a Congenital Dyserythropoietic AnemiaAmerican Journal of Human Genetics, 2010
- Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobinNature Genetics, 2010
- Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell diseaseProceedings of the National Academy of Sciences of the United States of America, 2010
- Transcriptional silencing of γ-globin by BCL11A involves long-range interactions and cooperation with SOX6Genes & Development, 2010
- Control of fetal hemoglobin: new insights emerging from genomics and clinical implicationsHuman Molecular Genetics, 2009
- Ikaros and GATA-1 Combinatorial Effect Is Required for Silencing of Human γ-Globin GenesMolecular and Cellular Biology, 2009
- DNA polymorphisms at the BCL11A , HBS1L-MYB , and β- globin loci associate with fetal hemoglobin levels and pain crises in sickle cell diseaseProceedings of the National Academy of Sciences of the United States of America, 2008
- Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of β-thalassemiaProceedings of the National Academy of Sciences of the United States of America, 2008
- Sequences Located 3′ to the Breakpoint of the Hereditary Persistence of Fetal Hemoglobin-3 Deletion Exhibit Enhancer Activity and Can Modify the Developmental Expression of the Human Fetal Aγ-Globin Gene in Transgenic MiceOnline Journal of Public Health Informatics, 1995