A functional element necessary for fetal hemoglobin silencing.

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.).

• Authors: Vijay G Sankaran, Jian Xu, Rachel Byron, Harvey A Greisman, Chris Fisher, David J Weatherall, Daniel E Sabath, Mark Groudine, Stuart H Orkin, Anuja Premawardhena, M A Bender
• Journal: The New England journal of medicine (N Engl J Med) Vol. 365 Issue 9 Pg. 807-14 (Sep 01 2011) ISSN: 1533-4406 [Electronic] United States
• PMID: 21879898 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Trans-Activators
• beta-Globins
• Fetal Hemoglobin

Topics

• Adult
• Child
• Chromatin Assembly and Disassembly
• Female
• Fetal Hemoglobin (genetics)
• Gene Deletion
• Gene Expression Regulation
• Gene Silencing
• Humans
• Male
• Pedigree
• Phenotype
• Trans-Activators
• beta-Globins (genetics)
• beta-Thalassemia (genetics)