title: 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: Department of Medicine, Children's Hospital Boston, Boston, MA 02115, USA. sankaran@broadinstitute.org
authors: Vijay G
authors: VG
authors: Sankaran
authors: Jian
authors: J
authors: Xu
authors: Rachel
authors: R
authors: Byron
authors: Harvey A
authors: HA
authors: Greisman
authors: Chris
authors: C
authors: Fisher
authors: David J
authors: DJ
authors: Weatherall
authors: Daniel E
authors: DE
authors: Sabath
authors: Mark
authors: M
authors: Groudine
authors: Stuart H
authors: SH
authors: Orkin
authors: Anuja
authors: A
authors: Premawardhena
authors: M A
authors: MA
authors: Bender
mesh_terms: D000328:Adult; D002648:Child; D042002:Chromatin Assembly and Disassembly; D005260:Female; D005319:Fetal Hemoglobin / Q000235:genetics*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype; D015534:Trans-Activators; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D015534:Trans-Activators; D055544:beta-Globins; D005319:Fetal Hemoglobin