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CRISPR-Cas9 globin editing can induce megabase-scale copy-neutral losses of heterozygosity in hematopoietic cells

dc.rights.licenseopenen_US
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorBOUTIN, Julian
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorROSIER, Juliette
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorCAPPELLEN, David
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorPRAT, Florence
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorTOUTAIN, Jerome
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorPENNAMEN, Perrine
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorBOURON, Julie
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorROORYCK-THAMBO, Caroline
hal.structure.identifierBordeaux Research In Translational Oncology [Bordeaux] [BaRITOn]
dc.contributor.authorMERLIO, Jean-Philippe
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorLAMRISSI, Isabelle
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorCULLOT, Gregoire
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorAMINTAS, Samuel
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorGUYONNET-DUPERAT, Veronique
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorGED, Cecile
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorBLOUIN, Jean Marc
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorRICHARD, Emmanuel
IDREF: 080889085
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorDABERNAT, Sandrine
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorMOREAU-GAUDRY, Francois
hal.structure.identifierBiothérapies des maladies génétiques et cancers
dc.contributor.authorBEDEL, Aurelie
dc.date.accessioned2021-10-26T08:04:05Z
dc.date.available2021-10-26T08:04:05Z
dc.date.issued2021-08-13
dc.identifier.issn2041-1723en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/112869
dc.description.abstractEnCRISPR-Cas9 is a promising technology for gene therapy. However, the ON-target genotoxicity of CRISPR-Cas9 nuclease due to DNA double-strand breaks has received little attention and is probably underestimated. Here we report that genome editing targeting globin genes induces megabase-scale losses of heterozygosity (LOH) from the globin CRISPR-Cas9 cut-site to the telomere (5.2 Mb). In established lines, CRISPR-Cas9 nuclease induces frequent terminal chromosome 11p truncations and rare copy-neutral LOH. In primary hematopoietic progenitor/stem cells, we detect 1.1% of clones (7/648) with acquired megabase LOH induced by CRISPR-Cas9. In-depth analysis by SNP-array reveals the presence of copy-neutral LOH. This leads to 11p15.5 partial uniparental disomy, comprising two Chr11p15.5 imprinting centers (H19/IGF2:IG-DMR/IC1 and KCNQ1OT1:TSS-DMR/IC2) and impacting H19 and IGF2 expression. While this genotoxicity is a safety concern for CRISPR clinical trials, it is also an opportunity to model copy-neutral-LOH for genetic diseases and cancers.
dc.description.sponsorshipGénotoxicité induite par CRISPR-CAS9en_US
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.title.enCRISPR-Cas9 globin editing can induce megabase-scale copy-neutral losses of heterozygosity in hematopoietic cells
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s41467-021-25190-6en_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologieen_US
dc.identifier.pubmed34389729en_US
bordeaux.journalNature Communicationsen_US
bordeaux.volume12en_US
bordeaux.hal.laboratoriesMaladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211en_US
bordeaux.issue1en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.identifier.funderIDAssociation Française contre les Myopathiesen_US
hal.identifierhal-03403276
hal.version1
hal.date.transferred2021-10-26T08:04:13Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Nature%20Communications&rft.date=2021-08-13&rft.volume=12&rft.issue=1&rft.eissn=2041-1723&rft.issn=2041-1723&rft.au=BOUTIN,%20Julian&ROSIER,%20Juliette&CAPPELLEN,%20David&PRAT,%20Florence&TOUTAIN,%20Jerome&rft.genre=article


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