Title: Chromosomal context and epigenetic mechanisms control the efficacy of genome editing by rare-cutting designer endonucleases
Authors: Daboussi, Fayza ×
Zaslavskiy, Mikhail
Poirot, Laurent
Loperfido, Mariana
Gouble, Agnès
Guyot, Valerie
Leduc, Sophie
Galetto, Roman
Grizot, Sylvestre
Oficjalska, Danusia
Perez, Christophe
Delacôte, Fabien
Dupuy, Aurélie
Chion-Sotinel, Isabelle
Le Clerre, Diane
Lebuhotel, Céline
Danos, Olivier
Lemaire, Frédéric
Oussedik, Kahina
Cédrone, Frédéric
Epinat, Jean-Charles
Smith, Julianne
Yáñez-Muñoz, Rafael J
Dickson, George
Popplewell, Linda
Koo, Taeyoung
Vandendriessche, Thierry
Chuah, Marinee
Duclert, Aymeric
Duchateau, Philippe
Pâques, Frédéric #
Issue Date: Jul-2012
Publisher: Oxford University Press
Series Title: Nucleic Acids Research vol:40 issue:13 pages:6367-6379
Abstract: The ability to specifically engineer the genome of living cells at precise locations using rare-cutting designer endonucleases has broad implications for biotechnology and medicine, particularly for functional genomics, transgenics and gene therapy. However, the potential impact of chromosomal context and epigenetics on designer endonuclease-mediated genome editing is poorly understood. To address this question, we conducted a comprehensive analysis on the efficacy of 37 endonucleases derived from the quintessential I-CreI meganuclease that were specifically designed to cleave 39 different genomic targets. The analysis revealed that the efficiency of targeted mutagenesis at a given chromosomal locus is predictive of that of homologous gene targeting. Consequently, a strong genome-wide correlation was apparent between the efficiency of targeted mutagenesis (≤ 0.1% to ≈ 6%) with that of homologous gene targeting (≤ 0.1% to ≈ 15%). In contrast, the efficiency of targeted mutagenesis or homologous gene targeting at a given chromosomal locus does not correlate with the activity of individual endonucleases on transiently transfected substrates. Finally, we demonstrate that chromatin accessibility modulates the efficacy of rare-cutting endonucleases, accounting for strong position effects. Thus, chromosomal context and epigenetic mechanisms may play a major role in the efficiency rare-cutting endonuclease-induced genome engineering.
ISSN: 0305-1048
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
× corresponding author
# (joint) last author

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