HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers

Ralph Stadhouders, Suleyman Aktuna, Supat Thongjuea, Ali Aghajanirefah, Farzin Pourfarzad, Wilfred van IJcken, Boris Lenhard, Helen Rooks, Steve Best, Stephan Menzel, Frank Grosveld, Swee Lay Thein*, Eric Soler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

141 Citations (Scopus)

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 beta-thalassemia disease severity.

Original languageEnglish
Pages (from-to)1699-1710
Number of pages12
JournalJournal of Clinical Investigation
Volume124
Issue number4
Early online date10 Mar 2014
DOIs
Publication statusPublished - 1 Apr 2014

Keywords

  • BETA-GLOBIN LOCUS
  • CHROMOSOME CONFORMATION CAPTURE
  • CAUSES HEREDITARY PERSISTENCE
  • GENOME-WIDE ASSOCIATION
  • C-MYB
  • GENE-EXPRESSION
  • ERYTHROID-DIFFERENTIATION
  • CHROMATIN INTERACTIONS
  • TRANSCRIPTION FACTORS
  • SPATIAL-ORGANIZATION

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