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

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...

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Bibliographic Details
Published in:Nature communications 2015-05, Vol.6 (1), p.7085-7085, Article 7085
Main Authors: Wienert, Beeke, Funnell, Alister P W, Norton, Laura J, Pearson, Richard C M, Wilkinson-White, Lorna E, Lester, Krystal, Vadolas, Jim, Porteus, Matthew H, Matthews, Jacqueline M, Quinlan, Kate G R, Crossley, Merlin
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Basic Helix-Loop-Helix Transcription Factors - genetics
Binding Sites
Chromatin - genetics
Dimerization
Fetal Hemoglobin - genetics
Gene Silencing
Genome
Humans
K562 Cells
Mice
Mice, Transgenic
Molecular Sequence Data
Mutagenesis, Site-Directed
Mutation
Point Mutation
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Proto-Oncogene Proteins - genetics
T-Cell Acute Lymphocytic Leukemia Protein 1
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Summary: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms8085