Figure 1

Possible mechanism for the downregulation of α-globin gene expression in Melanesian hemoglobin H (HbH) disease. (a) Schematic diagram of the human α-globin locus. The ζ-globin gene (the light-blue oval) is expressed in the embryonic stage of development and is silenced at around 6 to 8 weeks of gestation. The α-globin genes (the dark-blue ovals) are activated in fetal liver, and then in bone marrow in the adult. The physiological levels of α-like globin gene expression depend on the actions of upstream enhancers (HS-33 and HS-40) - mainly HS-40, which is located 40 kb 5' of the ζ-gene. The scale on the figure indicates distances in kilobases from the start of the α-gene cluster. The single nucleotide polymorphism (SNP) 195 is shown as a green circle. (b,c) A possible explanation for the SNP195 promoter-induced downregulation of the α-globin genes. Effective interaction between proteins bound by the enhancer (depicted schematically as a red circle indicating the range of influence of the enhancer) and the α-globin genes is essential for their high-level expression, and is accomplished by chromatin looping. (b) In the normal locus the SNP195 region is lightly acetylated and chromatin flexibility favors interaction between the enhancer and the α₁- and α₂-genes. (c) When the SNP195 promoter site (green circle) is activated in Melanesian HbH disease, histone acetylation is increased and the chromatin becomes more flexible as a consequence, resulting in a change in loop size. This change means that the enhancer now preferentially interacts with the new promoter, and no longer influences expression of the globin genes.