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- Title
HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers.
- Authors
Stadhouders, Ralph; Aktuna, Suleyman; Thongjuea, Supat; Aghajanirefah, Ali; Pourfarzad, Farzin; van IJcken, Wilfred; Lenhard, Boris; Rooks, Helen; Best, Steve; Menzel, Stephan; Grosveld, Frank; Thein, Swee Lay; Soler, Eric
- Abstract
Genetic studies have identified common variants within the intergenic region (HBSIL-MYB) between GTP-binding elongation factor HBSIL 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 HBSIL-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 HBSIL-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 HBSIL-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.
- Subjects
COMPLEMENTATION (Genetics); GUANOSINE triphosphate; G proteins; ONCOGENES; SICKLE cell anemia; BETA-Thalassemia; GENETICS
- Publication
Journal of Clinical Investigation, 2014, Vol 124, Issue 4, p1699
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI71520