Editing the genome to introduce a beneficial naturally occurring mutation associated with increased fetal globin

Abstract

Genetic disorders resulting from defects in the adult globin genes are among the most common inherited diseases. Symptoms worsen from birth as fetal γ-globin expression is silenced. Genome editing could permit the introduction of beneficial single-nucleotide variants to ameliorate symptoms. Here, as proof of concept, we introduce the naturally occurring Hereditary Persistance of Fetal Haemoglobin (HPFH) −175T>C point mutation associated with elevated fetal γ-globin into erythroid cell lines. We show that this mutation increases fetal globin expression through de novo recruitment of the activator TAL1 to promote chromatin looping of distal enhancers to the modified γ-globin promoter. Adult expression of fetal haemoglobin is beneficial and thus desirable in patients with haemoglobin disorders. Here the authors introduce a naturally occurring mutation in the γ-globinpromoter and show that it causes binding of an activator TAL1, chromosome looping and revival of fetal haemoglobin expression in erythroid cells.