Computational Analysis Concerning the Impact of DNA Accessibility on CRISPR-Cas9 Cleavage Efficiency.


Journal

Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581

Informations de publication

Date de publication:
08 01 2020
Historique:
received: 23 03 2019
revised: 26 09 2019
accepted: 10 10 2019
pubmed: 2 11 2019
medline: 22 12 2020
entrez: 2 11 2019
Statut: ppublish

Résumé

Defining the variables that impact the specificity of CRISPR/Cas9 has been a major research focus. Whereas sequence complementarity between guide RNA and target DNA substantially dictates cleavage efficiency, DNA accessibility of the targeted loci has also been hypothesized to be an important factor. In this study, functional data from two genome-wide assays, genome-wide, unbiased identification of DSBs enabled by sequencing (GUIDE-seq) and circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq), have been computationally analyzed in conjunction with DNA accessibility determined via DNase I-hypersensitive sequencing from the Encyclopedia of DNA Elements (ENCODE) Database and transcriptome from the Sequence Read Archive to determine whether cellular factors influence CRISPR-induced cleavage efficiency. CIRCLE-seq and GUIDE-seq datasets were selected to represent the absence and presence of cellular factors, respectively. Data analysis revealed that correlations between sequence similarity and CRISPR-induced cleavage frequency were altered by the presence of cellular factors that modulated the level of DNA accessibility. The above-mentioned correlation was abolished when cleavage sites were located in less accessible regions. Furthermore, CRISPR-mediated edits were permissive even at regions that were insufficient for most endogenous genes to be expressed. These results provide a strong basis to dissect the contribution of local chromatin modulation markers on CRISPR-induced cleavage efficiency.

Identifiants

pubmed: 31672284
pii: S1525-0016(19)30462-9
doi: 10.1016/j.ymthe.2019.10.008
pmc: PMC6953893
pii:
doi:

Substances chimiques

Chromatin 0
RNA, Guide 0
DNA 9007-49-2
CRISPR-Associated Protein 9 EC 3.1.-
Deoxyribonuclease I EC 3.1.21.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

19-28

Subventions

Organisme : NIMH NIH HHS
ID : P30 MH092177
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH110360
Pays : United States
Organisme : NIMH NIH HHS
ID : T32 MH079785
Pays : United States

Informations de copyright

Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

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Auteurs

Cheng-Han Chung (CH)

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA.

Alexander G Allen (AG)

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA.

Neil T Sullivan (NT)

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA.

Andrew Atkins (A)

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA.

Michael R Nonnemacher (MR)

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Brian Wigdahl (B)

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address: bw45@drexel.edu.

Will Dampier (W)

Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA; School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA 19104, USA. Electronic address: wnd22@drexel.edu.

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Classifications MeSH