3’HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression

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 prime 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.

Genom‐wide analysis identifies single nucleotide polymorphism variations and altered pathways associated with poor semen quality in breeding bulls

“…Also OR52A1 gene contains enhancer required for 3′HS1 CTCF binding site in beta-globin for fetal haemoglobin expression (Himadewi et al, 2021). In our study, we found OR52A1 gene with deleterious effect (0.…”

“…Individuals with deletion of OR52A1 genes were detected with Beta‐Thalassemia (Van Ziffle, Yang, & Chehab, 2011). Also OR52A1 gene contains enhancer required for 3′HS1 CTCF binding site in beta‐globin for fetal haemoglobin expression (Himadewi et al, 2021). In our study, we found OR52A1 gene with deleterious effect (0.04) had mutation (C > T) in chromosome 15 changing the amino acid sequence and possibly a change in the protein sequence.…”

Comprehensive analysis and accurate quantification of unintended large gene modifications induced by CRISPR-Cas9 gene editing

“…2D). Therefore, in addition to HBB KO or producing protein variants because of in-frame INDELs, LDs may induce HbF expression (46)(47)(48), similar to the naturally occurring HPFH. The 13-nt HPFH deletion in the HBG1 promoter has been actively pursued as a treatment strategy for -hemoglobinopathies (27).…”