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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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 1

The erythroid/hematopoietic-specific regulatory signature of the HBS1L-MYB intergenic region associated with HbF levels and other human erythroid traits.

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The erythroid/hematopoietic-specific regulatory signature of the HBS1L-M...
(A) Intergenic SNPs associated (P < 10–8) with different erythroid phenotypes (listed in Table 1) as reported by published GWAS (Table 1) are plotted below the HBS1L-MYB locus. (B) Locus-wide expression, DNaseI hypersensitivity, and enhancer chromatin signature data for 4 different cell types representing erythrocytes (K562), lymphocytes (Gm12878), endothelial cells (HUVEC) and keratinocytes (NHEK). The y axis represents sequence tag density. (C) Locus-wide digital genomic footprinting data shown for an erythroid cell line (K562) expressing both MYB and HBS1L (HBS1L pos/MYB pos) and for a liver cell line (HepG2) expressing only HBS1L (HBS1L pos/MYB neg). The y axis represents sequence tag density. Genome-wide data sets were obtained from the ENCODE consortium and accessed through the UCSC Genome Browser ( http://genome.ucsc.edu/). DNaseI-HS, DNaseI hypersensitivity.