Base-editing-mediated dissection of a γ-globin cis-regulatory element for the therapeutic reactivation of fetal hemoglobin expression

Panagiotis Antoniou, Giulia Hardouin, Pierre Martinucci, Giacomo Frati, Tristan Felix, Anne Chalumeau, Letizia Fontana, Jeanne Martin, Cecile Masson, Megane Brusson, Giulia Maule, Marion Rosello, Carine Giovannangeli, Vincent Abramowski, Jean-Pierre de Villartay, Jean-Paul Concordet, Filippo Del Bene, Wassim El Nemer, Mario Amendola, Marina Cavazzana, Anna Cereseto, Oriana Romano and Annarita Miccio ()
Additional contact information
Panagiotis Antoniou: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163
Giulia Hardouin: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163
Pierre Martinucci: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163
Giacomo Frati: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163
Tristan Felix: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163
Anne Chalumeau: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163
Letizia Fontana: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163
Jeanne Martin: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163
Cecile Masson: Bioinformatics Platform, Imagine Institute
Megane Brusson: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163
Giulia Maule: CIBIO, University of Trento
Marion Rosello: Sorbonne Université, INSERM, CNRS, Institut de la Vision
Carine Giovannangeli: INSERM U1154, CNRS UMR7196, Museum National d’Histoire Naturelle
Vincent Abramowski: Université Paris Cité, Imagine Institute, Laboratory of genome dynamics in the immune system, INSERM UMR 1163
Jean-Pierre de Villartay: Université Paris Cité, Imagine Institute, Laboratory of genome dynamics in the immune system, INSERM UMR 1163
Jean-Paul Concordet: INSERM U1154, CNRS UMR7196, Museum National d’Histoire Naturelle
Filippo Del Bene: Sorbonne Université, INSERM, CNRS, Institut de la Vision
Wassim El Nemer: Établissement Français du Sang, UMR 7268
Mario Amendola: Genethon
Marina Cavazzana: Assistance Publique Hopitaux de Paris, INSERM
Anna Cereseto: CIBIO, University of Trento
Oriana Romano: University of Modena and Reggio Emilia
Annarita Miccio: Université Paris Cité, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract Sickle cell disease and β-thalassemia affect the production of the adult β-hemoglobin chain. The clinical severity is lessened by mutations that cause fetal γ-globin expression in adult life (i.e., the hereditary persistence of fetal hemoglobin). Mutations clustering ~200 nucleotides upstream of the HBG transcriptional start sites either reduce binding of the LRF repressor or recruit the KLF1 activator. Here, we use base editing to generate a variety of mutations in the −200 region of the HBG promoters, including potent combinations of four to eight γ-globin-inducing mutations. Editing of patient hematopoietic stem/progenitor cells is safe, leads to fetal hemoglobin reactivation and rescues the pathological phenotype. Creation of a KLF1 activator binding site is the most potent strategy – even in long-term repopulating hematopoietic stem/progenitor cells. Compared with a Cas9-nuclease approach, base editing avoids the generation of insertions, deletions and large genomic rearrangements and results in higher γ-globin levels. Our results demonstrate that base editing of HBG promoters is a safe, universal strategy for treating β-hemoglobinopathies.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-34493-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34493-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-34493-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().