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.

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