A functional element necessary for fetal hemoglobin silencing.

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 ?-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 ?-globin gene (?-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 ?-globin locus by using chromatin immunoprecipitation.We found a new (??)(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 ?-globin (fetal hemoglobin) gene silencing. We mapped a Kurdish ?(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 ?-globin gene that is necessary for ?-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 ?-globin locus, we identified an intergenic region near the ?-globin gene that is necessary for fetal hemoglobin silencing. (Funded by the National Institutes of Health and others.).

SUBMITTER: Sankaran VG 

PROVIDER: S-EPMC3174767 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature