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

Beeke Wienert, Alister P W Funnell, Laura J. Norton, Richard C M Pearson, Lorna E. Wilkinson-White, Krystal Lester, Jim Vadolas, Matthew H. Porteus, Jacqueline M. Matthews, Kate G R Quinlan, Merlin Crossley

Research output: Contribution to journalArticleResearchpeer-review

64 Citations (Scopus)

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.

Original languageEnglish
Article number7085
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 14 May 2015
Externally publishedYes

Cite this