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

doi:10.1038/ncomms8085

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

Nat Commun. 2015 May 14:6:7085. doi: 10.1038/ncomms8085.

Affiliations

¹ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
² School of Molecular Bioscience, The University of Sydney, Sydney, New South Wales 2006, Australia.
³ 1] Cell and Gene Therapy Research Group, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia [2] Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia.
⁴ Department of Pediatrics, Stanford University, Stanford, California 94304, USA.

PMID: 25971621
DOI: 10.1038/ncomms8085

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Basic Helix-Loop-Helix Transcription Factors
Chromatin
Proto-Oncogene Proteins
T-Cell Acute Lymphocytic Leukemia Protein 1
Tal1 protein, mouse
TAL1 protein, human
Fetal Hemoglobin