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

Genetic studies have identified common variants within the HBS1L-MYB intergenic region on chromosome 6q associated with elevated fetal hemoglobin (HbF) levels and other clinically important human erythroid traits. The mechanism by which the non-coding sequence variants affect these traits is still not clear. Here we report that several of the 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 show that several of the variants reduce transcription factor binding, affecting long-range interactions with MYB, and MYB expression levels. We provide here 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 bona fide target for therapeutic induction of HbF to ameliorate sickle cell and ß-thalassemia disease severity. Overall design: ChIP-Sequencing profiles of the LDB1 and CTCF proteins were generated using primary human erythroid progenitors. 3C-Seq experiments (in duplicate, primary human erythroid progenitors) were performed using the MYB promoter and the -84kb upstream enhancer as viewpoints.