title: HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers.
abstract: 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.
authors.forename: Ralph
authors.initials: R
authors.lastname: Stadhouders
authors.forename: Suleyman
authors.initials: S
authors.lastname: Aktuna
authors.forename: Supat
authors.initials: S
authors.lastname: Thongjuea
authors.forename: Ali
authors.initials: A
authors.lastname: Aghajanirefah
authors.forename: Farzin
authors.initials: F
authors.lastname: Pourfarzad
authors.forename: Wilfred
authors.initials: W
authors.lastname: van Ijcken
authors.forename: Boris
authors.initials: B
authors.lastname: Lenhard
authors.forename: Helen
authors.initials: H
authors.lastname: Rooks
authors.forename: Steve
authors.initials: S
authors.lastname: Best
authors.forename: Stephan
authors.initials: S
authors.lastname: Menzel
authors.forename: Frank
authors.initials: F
authors.lastname: Grosveld
authors.forename: Swee Lay
authors.initials: SL
authors.lastname: Thein
authors.forename: Eric
authors.initials: E
authors.lastname: Soler
mesh_terms: D000328:Adult; D002460:Cell Line; D021901:DNA, Intergenic / Q000235:genetics* / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D041905:Erythroid Cells / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics*; D020570:Genes, myb; D014644:Genetic Variation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D020014:K562 Cells; D010445:Peptide Elongation Factors / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D021901:DNA, Intergenic; D018840:HSP70 Heat-Shock Proteins; D010445:Peptide Elongation Factors; D014157:Transcription Factors; D005319:Fetal Hemoglobin; D019204:GTP-Binding Proteins; C000628258:HBS1L protein, human