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Induction of fetal hemoglobin synthesis by CRISPR/Cas9-mediated editing of the human beta-globin locus
- Source :
- Blood, Blood, American Society of Hematology, 2018, 131, pp.1960-1973. ⟨10.1182/blood-2017-10-811505⟩, Blood, 2018, 131, pp.1960-1973. ⟨10.1182/blood-2017-10-811505⟩
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
Abstract
- International audience; Naturally occurring, large deletions in the beta-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle cell disease (SCD) and beta-thalassemia. We designed a clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) strategy to disrupt a 13.6-kb genomic region encompassing the delta- and beta-globin genes and a putative gamma-delta intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in gamma-globin expression, whereas deletion or inversion of a 13.6-kb region causes a robust reactivation of HbF synthesis in adult erythroblasts that is associated with epigenetic modifications and changes in chromatin contacts within the beta-globin locus. In primary SCD patient-derived hematopoietic stem/progenitor cells, targeting the 13.6-kb region results in a high proportion of gamma-globin expression in erythroblasts, increased HbF synthesis, and amelioration of the sickling cell phenotype. Overall, this study provides clues for a potential CRISPR/Cas9 genome editing approach to the therapy of beta-hemoglobinopathies.
- Subjects :
- 0301 basic medicine
Cell Line
Hematopoietic Stem Cells
Humans
beta-Globins
Anemia, Sickle Cell
CRISPR-Cas Systems
Fetal Hemoglobin
Gene Editing
Genetic Loci
congenital, hereditary, and neonatal diseases and abnormalities
Hereditary persistence of fetal hemoglobin
[SDV]Life Sciences [q-bio]
Immunology
Biology
Biochemistry
03 medical and health sciences
Human β-globin locus
hemic and lymphatic diseases
Fetal hemoglobin
medicine
CRISPR
Globin
Epigenetics
Genetics
Cas9
Anemia
Cell Biology
Hematology
medicine.disease
Chromatin
Sickle Cell
030104 developmental biology
BLOOD Commentary
Subjects
Details
- Language :
- English
- ISSN :
- 00064971 and 15280020
- Database :
- OpenAIRE
- Journal :
- Blood, Blood, American Society of Hematology, 2018, 131, pp.1960-1973. ⟨10.1182/blood-2017-10-811505⟩, Blood, 2018, 131, pp.1960-1973. ⟨10.1182/blood-2017-10-811505⟩
- Accession number :
- edsair.doi.dedup.....b4b03950f429c7272d83511e6c369566