title: 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.
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Beeke
authors.initials: B
authors.lastname: Wienert
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Alister P W
authors.initials: AP
authors.lastname: Funnell
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Norton
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Richard C M
authors.initials: RC
authors.lastname: Pearson
authors.affiliation: School of Molecular Bioscience, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Lorna E
authors.initials: LE
authors.lastname: Wilkinson-White
authors.affiliation: School of Molecular Bioscience, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Krystal
authors.initials: K
authors.lastname: Lester
authors.affiliation: 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.
authors.forename: Jim
authors.initials: J
authors.lastname: Vadolas
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California 94304, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Porteus
authors.affiliation: School of Molecular Bioscience, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Matthews
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Kate G R
authors.initials: KG
authors.lastname: Quinlan
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Merlin
authors.initials: M
authors.lastname: Crossley
mesh_terms: D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001665:Binding Sites; D002843:Chromatin / Q000235:genetics; D019281:Dimerization; D005319:Fetal Hemoglobin / Q000235:genetics*; D020868:Gene Silencing; D016678:Genome; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D005319:Fetal Hemoglobin; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human