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Genetic studies have identified common variants within the intergenic region (HBS1L-MYB) between GTP-binding elongation factor HBS1L and myeloblastosis oncogene MYB on chromosome 6q that are associated with elevated fetal hemoglobin (HbF) levels and alterations of other clinically important human erythroid traits. It is unclear how these noncoding sequence variants affect multiple erythrocyte characteristics. Here, we determined that several HBS1L-MYB intergenic variants affect regulatory elements that are occupied by key erythroid transcription factors within this region. These elements interact with MYB, a critical regulator of erythroid development and HbF levels. We found that several HBS1L-MYB intergenic variants reduce transcription factor binding, affecting long-range interactions with MYB and MYB expression levels. These data provide a functional explanation for the genetic association of HBS1L-MYB intergenic polymorphisms with human erythroid traits and HbF levels. Our results further designate MYB as a target for therapeutic induction of HbF to ameliorate sickle cell and β-thalassemia disease severity.

Original publication

DOI

10.1172/JCI71520

Type

Journal article

Journal

J Clin Invest

Publication Date

04/2014

Volume

124

Pages

1699 - 1710

Keywords

Adult, Cell Line, DNA, Intergenic, Enhancer Elements, Genetic, Erythroid Cells, Fetal Hemoglobin, GTP-Binding Proteins, Genes, myb, Genetic Variation, HSP70 Heat-Shock Proteins, Humans, K562 Cells, Peptide Elongation Factors, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Transcription Factors