CRISPR-Cas systems articles within Nature Communications

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  • Article
    | Open Access

    Polymerase theta is a widely conserved DNA polymerase that mediates Theta Mediated End Joining. Here authors present a synthetic lethal CRISPR screen to identify DDR gene mutations that induce cellular addiction to Pol theta.

    • Wanjuan Feng
    • , Dennis A. Simpson
    •  & Gaorav P. Gupta

  • Article
    | Open Access

    The role of CTCF-bound insulator elements in enhancer-gene interactions and transcriptional regulation remains poorly understood. Here, the authors investigate multiple epigenome editing strategies for perturbing individual CTCF-bound insulators, and evaluate their effects on genome topology and transcription.

    • Daniel R. Tarjan
    • , William A. Flavahan
    •  & Bradley E. Bernstein

  • Article
    | Open Access

    CRISPR-Cas9 genome editing is presumed to knock out gene function by generating a frameshift during NHEJ repair. Here, the authors investigate mRNA and protein expression in edited lines and find genome editing can generate internal ribosome entry sites or alternatively spliced variants.

    • Rubina Tuladhar
    • , Yunku Yeu
    •  & Lawrence Lum

  • Article
    | Open Access

    Off-target effects in CRISPR screens for essential regulatory elements have not been systematically evaluated. Here the authors find Cas9 nuclease, CRISPRi/a each have distinct off-target effects, and that these can be accurately identified and removed using the GuideScan sgRNA specificity score.

    • Josh Tycko
    • , Michael Wainberg
    •  & Michael C. Bassik

  • Article
    | Open Access

    Mucopolysaccharidosis type I (MPSI) is a lysosomal storage disease caused by insufficient iduronidase (IDUA) activity. Here, the authors use an ex vivo genome editing approach to overexpress IDUA in human hematopoietic stem and progenitor cells and show it can phenotypically correct MSPI in mouse model.

    • Natalia Gomez-Ospina
    • , Samantha G. Scharenberg
    •  & Matthew H. Porteus

  • Article
    | Open Access

    Cytosine base editors are limited by editing scope and potential off-target effects. Here the authors screen diversified lamprey cytidine deaminases along with different protein fusion architectures and present base editors with improved fidelity.

    • Tian-Lin Cheng
    • , Shuo Li
    •  & Zilong Qiu

  • Article
    | Open Access

    Single-particle tracking PALM (sptPALM) provides quantitative information in vivo if the protein of interest remains in a single diffusional state during track acquisition. Here the authors develop a custom-built sptPALM microscope and a Monte-Carlo based diffusion distribution analysis to study dynamic DNA-dCas9 interactions in live bacteria.

    • Koen J. A. Martens
    • , Sam P. B. van Beljouw
    •  & Johannes Hohlbein

  • Article
    | Open Access

    Cystic fibrosis is caused by mutations in the CFTR chloride channel. Here, the authors develop a gene therapy approach using the programmable nuclease AsCas12a to correct a splicing mutation in CFTR, and show efficient repair of the mutation and recovery of CFTR function in patient-derived organoids and airway epithelial cells.

    • Giulia Maule
    • , Antonio Casini
    •  & Anna Cereseto

  • Article
    | Open Access

    Functional variants have been proposed to alter transcription factor binding. Here, the authors provide direct evidence that functional variants within the TBC1D4 gene, encoding an NFκB binding site, can alter transcription factor binding, and use CRISPR-Cas9 to reveal localization of the transcription factor to be the regulator of chromatin accessibility and p65 binding and ultimately TBC1D4 expression.

    • Andrew D. Johnston
    • , Claudia A. Simões-Pires
    •  & John M. Greally

  • Article
    | Open Access

    Conventional methods to detect AAV vector transduction can miss transient or low levels of reporter expression. Here the authors use editing-reporter mice and discover numerous sites of AAV targeting along with better prediction of the gene editing footprint.

    • Jonathan F. Lang
    • , Sushila A. Toulmin
    •  & Beverly L. Davidson

  • Article
    | Open Access

    Type 2 diabetes (T2D) is prevalent in populations worldwide, however, mostly studied in European and mixed-ancestry populations. Here, the authors perform a genome-wide association study for T2D in over 5,000 sub-Saharan Africans and identify a locus, ZRANB3, that is specific for this population.

    • Adebowale A. Adeyemo
    • , Norann A. Zaghloul
    •  & Charles N. Rotimi

  • Article
    | Open Access

    AsCpf1 is an alternative nuclease to Cas9 for CRISPR mediated genome engineering. Here the authors demonstrate functional genomic screens with AsCpf1 that minimize library size with no loss in gene targeting efficiency.

    • Jintan Liu
    • , Sanjana Srinivasan
    •  & Giulio Draetta

  • Article
    | Open Access

    Type III CRISPR-Cas systems are able to target transcriptionally active DNA sequences in phages and plasmids. Here, the authors reveal the mechanism of the target nucleic acid preference of Type III-A CRISPR-Cas complexes at the transcription bubble by a combination of structural and biochemical approaches.

    • Tina Y. Liu
    • , Jun-Jie Liu
    •  & Jennifer A. Doudna

  • Article
    | Open Access

    Here, the authors show that sequential treatment with long-acting slow-effective release ART and AAV9- based delivery of CRISPR-Cas9 results in undetectable levels of virus and integrated DNA in a subset of humanized HIV-1 infected mice. This proof-of-concept study suggests that HIV-1 elimination is possible.

    • Prasanta K. Dash
    • , Rafal Kaminski
    •  & Howard E. Gendelman

  • Article
    | Open Access

    Cas13d is a class 2 type VI-D CRISPR-Cas RNA-guided RNase. Here the authors present the high-resolution crystal structure of the uncultured Ruminococcus sp. Cas13d (UrCas13d)-crRNA complex and by combining structural, mutational and biochemical studies provide mechanistic insights into the CRISPR-Cas13d system.

    • Bo Zhang
    • , Yangmiao Ye
    •  & Songying Ouyang

  • Article
    | Open Access

    Wwp2 is an HECT-type E3 ubiquitin ligase abundantly expressed in articular cartilage. Here, the authors show that in mice, loss of Wwp2 leads to upregulated Runx2-Adamts5 signaling in articular cartilage and development of osteoarthritis, and that disease severity is reduced by injection of Wwp2 mRNA

    • Sho Mokuda
    • , Ryo Nakamichi
    •  & Hiroshi Asahara

  • Article
    | Open Access

    Master transcription factors dominantly direct cell fate and barriers ensuring their tissue specific silencing are not clearly defined. Here, the authors demonstrate that inefficient targeted transactivation of Sox1 in neural progenitor cells is surmountable through targeted promoter demethylation using dCas9-Tet1.

    • Valentin Baumann
    • , Maximilian Wiesbeck
    •  & Stefan H. Stricker

  • Review Article
    | Open Access

    Generation of transgenic mice has become routine in studying gene function and disease mechanisms, but often this is not enough to fully understand human biology. Here, the authors review the current state of the art of targeted genomic humanisation strategies and their advantages over classic approaches.

    • Fei Zhu
    • , Remya R. Nair
    •  & Thomas J. Cunningham

  • Article
    | Open Access

    Possible immunogenicity of the Cas9 protein raises concerns about therapeutic applications. Here the authors identify pre-existing CD8+T-cell immunity in healthy individuals and in response modify Cas9 to remove the immunodominant epitopes.

    • Shayesteh R. Ferdosi
    • , Radwa Ewaisha
    •  & Karen S. Anderson

  • Article
    | Open Access

    Gene-drives use CRISPR-Cas9 to be transmitted in a super-Mendelian fashion. Here the authors develop an allelic-drive for selective inheritance of a desired allele.

    • Annabel Guichard
    • , Tisha Haque
    •  & Ethan Bier

  • Article
    | Open Access

    Gene correction in hematopoietic stem cells could be a powerful way to treat monogenic diseases of the blood and immune system. Here the authors develop a strategy using CRISPR-Cas9 and an aAdeno-Associated vVirus(AAV)-delivered IL2RG cDNA to correct X-linked sSevere Ccombined iImmunodeficiency (SCID-X1) with a high success rate.

    • Mara Pavel-Dinu
    • , Volker Wiebking
    •  & Matthew H. Porteus

  • Article
    | Open Access

    Designing effective genome engineering strategies requires an understanding of the impact that genomic locus has on CRISPR-Cas9 activity. Here the authors use TRIP integrations to profile editing outcomes genome-wide and observe that gRNA sequence influences the structure of the double strand break.

    • Santiago Gisler
    • , Joana P. Gonçalves
    •  & Maarten van Lohuizen

  • Article
    | Open Access

    CRISPR-Cas9 has been rapidly adopted to generate cell line models of disease. Here the authors show, while attempting to establish a congenital erythropoietic porphyria model, unexpected chromosome truncations generated by a p53-dependent mechanism.

    • Grégoire Cullot
    • , Julian Boutin
    •  & Aurélie Bedel

  • Article
    | Open Access

    Analogue regulation of gene expression is important for normal function in mammals but existing genetic technologies are designed to achieve ON/OFF control. Here the authors develop synthetic microRNA silencing-mediated fine-tuners (miSFITs) to precisely control target gene expression levels.

    • Yale S. Michaels
    • , Mike B. Barnkob
    •  & Tudor A. Fulga

  • Article
    | Open Access

    Few approaches for targeted manipulation of the epigenome are available in plants. Here, the authors adapt the dCas9-SunTag system to engineer targeted gene activation and site-specific manipulation of DNA methylation in Arabidopsis.

    • Ashot Papikian
    • , Wanlu Liu
    •  & Steven E. Jacobsen

  • Article
    | Open Access

    The genomic locations that can be targeted for editing by CRISPR are limited by the presence of the nuclease-specific PAM sequence. Here, the authors show PAM recognition can be expanded by replacing the key region in the PAM interaction domain of SaCas9 with the corresponding region of SaCas9 orthologs.

    • Dacheng Ma
    • , Zhimeng Xu
    •  & Zhen Xie

  • Article
    | Open Access

    Multiple morphological abnormalities of the sperm flagella (MMAF) is a cause of male infertility. Here the authors identify homozygous nonsense mutations of the glutamine rich 2 (QRICH2) gene in two MMAF patients from 2 consanguineous families and show using QRICH2 knockout mice that the protein is required for sperm flagellar formation and motility.

    • Ying Shen
    • , Feng Zhang
    •  & Wenming Xu

  • Article
    | Open Access

    It is difficult to identify cancer driver genes in cancers, for instance BRCA1 mutated breast cancer, that are characterised by large scale genomic alterations. Here, the authors develop genetically engineered mouse models of BRCA1-deficient breast cancer that allow highthroughput in vivo perturbation of candidate driver genes, validating drivers Myc, Met, Pten and Rb1, and identifying MCL1 as a collaborating driver whose targeting can impact efficacy of PARP inhibition.

    • Stefano Annunziato
    • , Julian R. de Ruiter
    •  & Jos Jonkers

  • Article
    | Open Access

    The Cas12b family of CRISPR nucleases has been underutilized in mammalian cells due to the high temperature requirement of known members. Here the authors engineer BhCas12b to overcome this limitation for robust and specific genome editing applications in human cells.

    • Jonathan Strecker
    • , Sara Jones
    •  & Feng Zhang

  • Article
    | Open Access

    Adenine base editors are an important contribution to the genome editing toolbox. Here the authors present EndoV-seq, an endonuclease-based assay for evaluating genomewide off-target effects of base editing.

    • Puping Liang
    • , Xiaowei Xie
    •  & Zhou Songyang

  • Article
    | Open Access

    A current challenge in genome editing is delivering Cas9 and sgRNA into target cells. Here the authors engineer a delivery system based on murine leukemia virus-like particles loaded with Cas9-sgRNA ribonucleoproteins to induce efficient genome editing in both cell culture and in vivo in mouse.

    • Philippe E. Mangeot
    • , Valérie Risson
    •  & Emiliano P. Ricci

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