HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers
Ralph Stadhouders, … , Swee Lay Thein, Eric Soler
Ralph Stadhouders, … , Swee Lay Thein, Eric Soler
Published March 10, 2014
Citation Information: J Clin Invest. 2014;124(4):1699-1710. https://doi.org/10.1172/JCI71520.
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Research Article Hematology

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

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

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Figure 2

The HBS1L-MYB intergenic region contains regulatory elements bound by erythroid TFs.

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The HBS1L-MYB intergenic region contains regulatory elements bound by er...
(A) LDB1 ChIP-Seq data from primary HEPs. LDB1 peaks were marked by their distance to the MYB TSS. (B and C) ChIP-qPCR data (HEPs) showing enrichment (n = 3) for LDB1 complex members (B) and KLF1 (C) at the intergenic binding sites. IgG serum was used as control (IgG); the HBG1/2 promoter for normalization. (D) Comparison of mouse and human LDB1 ChIP-Seq data from erythroid progenitors. Binding sites not conserved are marked (*). The region containing the 4 conserved sites (conserved core) is highlighted in purple. Error bars display SEM. FL E13.5, 13.5 dpc fetal liver erythroid progenitors.