Abstract
Mutations in the adult β-globin gene can lead to a variety of hemoglobinopathies, including sickle cell disease and β-thalassemia. An increase in fetal hemoglobin expression throughout adulthood, a condition named hereditary persistence of fetal hemoglobin (HPFH), has been found to ameliorate hemoglobinopathies. Deletional HPFH occurs through the excision of a significant portion of the 3' end of the β-globin locus, including a CTCF binding site termed 3'HS1. Here, we show that the deletion of this CTCF site alone induces fetal hemoglobin expression in both adult CD34+ hematopoietic stem and progenitor cells and HUDEP-2 erythroid progenitor cells. This induction is driven by the ectopic access of a previously postulated distal enhancer located in the OR52A1 gene downstream of the locus, which can also be insulated by the inversion of the 3'HS1 CTCF site. This suggests that genetic editing of this binding site can have therapeutic implications to treat hemoglobinopathies.
Highlights
The human β-globin locus consists of five globin genes embedded in the olfactory receptor cluster
Inherited mutations in the HBB gene lead to dysfunction of the adult β-globin protein, causing hemoglobinopathies (Bauer et al, 2012). The symptoms of these disorders, including sickle cell disease and β-thalassemia, can be alleviated by persistent expression of fetal hemoglobin throughout adulthood, which compensates for the mutant adult β-globin (Bank, 2006; Hassell, 2010)
The human β-globin gene locus is flanked by five CTCF binding sites (CBSs), which form the anchors for six chromosomal loops (Huang et al, 2017)
Summary
The human β-globin locus consists of five globin genes embedded in the olfactory receptor cluster. Inherited mutations in the HBB gene lead to dysfunction of the adult β-globin protein, causing hemoglobinopathies (Bauer et al, 2012). The symptoms of these disorders, including sickle cell disease and β-thalassemia, can be alleviated by persistent expression of fetal hemoglobin (hereditary persistence of fetal hemoglobin [HPFH]) throughout adulthood, which compensates for the mutant adult β-globin (Bank, 2006; Hassell, 2010). Chromosomes and Gene Expression | Genetics and Genomics (Forget, 1998; Ye et al, 2016) These deletions can vary in length, and it remains unclear as to how they lead to the expression of fetal globin in adulthood (Ye et al, 2016)
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