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Inducible crispr

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https://www.readbyqxmd.com/read/28102837/precise-and-efficient-scarless-genome-editing-in-stem-cells-using-correct
#1
Dylan Kwart, Dominik Paquet, Shaun Teo, Marc Tessier-Lavigne
CRISPR/Cas9 is a promising tool for genome-editing DNA in cells with single-base-pair precision, which allows novel in vitro models of human disease to be generated-e.g., in pluripotent stem cells. However, the accuracy of intended sequence changes can be severely diminished by CRISPR/Cas9's propensity to re-edit previously modified loci, causing unwanted mutations (indels) alongside intended changes. Here we describe a genome-editing framework termed consecutive re-guide or re-Cas steps to erase CRISPR/Cas-blocked targets (CORRECT), which, by exploiting the use of highly efficacious CRISPR/Cas-blocking mutations in two rounds of genome editing, enables accurate, efficient and scarless introduction of specific base changes-for example, in human induced pluripotent (iPS) stem cells...
February 2017: Nature Protocols
https://www.readbyqxmd.com/read/28095751/crispr-based-epigenome-editing-of-cytokine-receptors-for-the-promotion-of-cell-survival-and-tissue-deposition-in-inflammatory-environments
#2
Niloofar Farhang, Jonathan M Brunger, Joshua D Stover, Pratiksha I Thakore, Brandon Lawrence, Farshid Guilak, Charles A Gersbach, Lori A Setton, Robert D Bowles
Musculoskeletal diseases have been associated with inflammatory cytokine action, particularly action by TNF-α and IL-1β. These inflammatory cytokines promote apoptosis and senescence of cells in diseased tissue and extracellular matrix breakdown. Stem cell-based therapies are being considered for the treatment of musculoskeletal diseases, but the presence of these inflammatory cytokines will have similar deleterious action on therapeutic cells delivered to these environments. Methods that prevent inflammatory-induced apoptosis and pro-inflammatory signaling, in cell and pathway specific manners are needed...
January 17, 2017: Tissue Engineering. Part A
https://www.readbyqxmd.com/read/28090699/modelling-irf8-deficient-human-hematopoiesis-and-dendritic-cell-development-with-engineered-ips-cells
#3
Stephanie Sontag, Malrun Förster, Jie Qin, Paul Wanek, Saskia Mitzka, Herdit M Schüler, Steffen Koschmieder, Stefan Rose-John, Kristin Seré, Martin Zenke
Human induced pluripotent stem (iPS) cells can differentiate into cells of all three germ layers, including hematopoietic stem cells and their progeny. Interferon regulatory factor 8 (IRF8) is a transcription factor, which acts in hematopoiesis as lineage determining factor for myeloid cells, including dendritic cells (DC). Autosomal recessive or dominant IRF8 mutations occurring in patients cause severe monocytic and DC immunodeficiency. To study IRF8 in human hematopoiesis we generated human IRF8-/- iPS cells and IRF8-/- embryonic stem (ES) cells using RNA guided CRISPR/Cas9n genome editing...
January 16, 2017: Stem Cells
https://www.readbyqxmd.com/read/28088877/the-concerted-action-of-type-2-and-type-3-deiodinases-regulates-the-cell-cycle-and-survival-of-basal-cell-carcinoma-cells
#4
Caterina Miro, Raffaele Ambrosio, Maria Angela De Stefano, Daniela Di Girolamo, Emery Di Cicco, Annunziata Gaetana Cicatiello, Giuseppina Mancino, Tommaso Porcelli, Maddalena Raia, Luigi Del Vecchio, Domenico Salvatore, Monica Dentice
BACKGROUND: Thyroid hormones (THs) mediate pleiotropic cellular processes involved in metabolism, cellular proliferation and differentiation. The intracellular hormonal environment can be tailored by the deiodinase enzymes, D2 and D3, which catalyze TH activation and inactivation, respectively. In many cellular systems, THs exert well documented stimulatory or inhibitory effects on cell proliferation, however, the molecular mechanisms by which they control rates of cell cycle progression have not yet been entirely clarified...
January 15, 2017: Thyroid: Official Journal of the American Thyroid Association
https://www.readbyqxmd.com/read/28073774/temporally-distinct-pd-l1-expression-by-tumor-and-host-cells-contributes-to-immune-escape
#5
Takuro Noguchi, Jeffrey P Ward, Matthew M Gubin, Cora D Arthur, Sang Hun Lee, Jasreet Hundal, Mark Selby, Robert F Graziano, Elaine R Mardis, Alan J Korman, Robert D Schreiber
Antibody blockade of Programmed Death-1 (PD-1) or its ligand, PD-L1, has led to unprecedented therapeutic responses in certain tumor-bearing individuals, but PD-L1 expression's prognostic value in stratifying cancer patients for such treatment remains unclear. Reports conflict on the significance of correlations between PD-L1 on tumor cells and positive clinical outcomes to PD-1/PD-L1 blockade. We investigated this issue using genomically-related, clonal subsets from the same methylcholanthrene-induced sarcoma: a highly immunogenic subset that is spontaneously eliminated in vivo by adaptive immunity and a less immunogenic subset that forms tumors in immunocompetent mice, but is sensitive to PD-1/PD-L1 blockade therapy...
January 10, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28069571/apc-c-dysfunction-limits-excessive-cancer-chromosomal-instability
#6
Laurent Sansregret, James O Patterson, Sally Dewhurst, Carlos López-García, André Koch, Nicholas McGranahan, William Chong Hang Chao, David J Barry, Andrew Rowan, Rachael Instrell, Stuart Horswell, Michael Way, Michael Howell, Martin R Singleton, René H Medema, Paul Nurse, Mark Petronczki, Charles Swanton
: Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization...
January 9, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28069043/fgf19-fgfr4-signaling-contributes-to-the-resistance-of-hepatocellular-carcinoma-to-sorafenib
#7
Lixia Gao, Xuli Wang, Yaoliang Tang, Shuang Huang, Chien-An Andy Hu, Yong Teng
BACKGROUND: Sorafenib, a multi-kinase inhibitor, is used as a standard therapy for advanced hepatocellular carcinoma (HCC). However, complete remission has not been achieved and the molecular basis of HCC resistance to sorafenib remains largely unknown. Previous studies have shown that fibroblast growth factor 19 (FGF19) expression correlates with tumor progression and poor prognosis of HCC. Here, we demonstrate the novel role of FGF19 in HCC resistance to sorafenib therapy. METHODS: FGF19 Knockdown cells were achieved by lentiviral-mediated interference, and FGFR4 knockout cells were achieved by CRISPR-Cas9...
January 9, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28068387/enhancing-targeted-genomic-dna-editing-in-chicken-cells-using-the-crispr-cas9-system
#8
Ling Wang, Likai Yang, Yijie Guo, Weili Du, Yajun Yin, Tao Zhang, Hongzhao Lu
The CRISPR/Cas9 system has enabled highly efficient genome targeted editing for various organisms. However, few studies have focused on CRISPR/Cas9 nuclease-mediated chicken genome editing compared with mammalian genomes. The current study combined CRISPR with yeast Rad52 (yRad52) to enhance targeted genomic DNA editing in chicken DF-1 cells. The efficiency of CRISPR/Cas9 nuclease-induced targeted mutations in the chicken genome was increased to 41.9% via the enrichment of the dual-reporter surrogate system...
2017: PloS One
https://www.readbyqxmd.com/read/28067901/targeting-samhd1-with-the-vpx-protein-to-improve-cytarabine-therapy-for-hematological-malignancies
#9
Nikolas Herold, Sean G Rudd, Linda Ljungblad, Kumar Sanjiv, Ida Hed Myrberg, Cynthia B J Paulin, Yaser Heshmati, Anna Hagenkort, Juliane Kutzner, Brent D G Page, José M Calderón-Montaño, Olga Loseva, Ann-Sofie Jemth, Lorenzo Bulli, Hanna Axelsson, Bianca Tesi, Nicholas C K Valerie, Andreas Höglund, Julia Bladh, Elisée Wiita, Mikael Sundin, Michael Uhlin, Georgios Rassidakis, Mats Heyman, Katja Pokrovskaja Tamm, Ulrika Warpman-Berglund, Julian Walfridsson, Sören Lehmann, Dan Grandér, Thomas Lundbäck, Per Kogner, Jan-Inge Henter, Thomas Helleday, Torsten Schaller
The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP), which causes DNA damage through perturbation of DNA synthesis. Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment...
January 9, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28067217/characterization-of-the-interplay-between-dna-repair-and-crispr-cas9-induced-dna-lesions-at-an-endogenous-locus
#10
Anne Bothmer, Tanushree Phadke, Luis A Barrera, Carrie M Margulies, Christina S Lee, Frank Buquicchio, Sean Moss, Hayat S Abdulkerim, William Selleck, Hariharan Jayaram, Vic E Myer, Cecilia Cotta-Ramusino
The CRISPR-Cas9 system provides a versatile toolkit for genome engineering that can introduce various DNA lesions at specific genomic locations. However, a better understanding of the nature of these lesions and the repair pathways engaged is critical to realizing the full potential of this technology. Here we characterize the different lesions arising from each Cas9 variant and the resulting repair pathway engagement. We demonstrate that the presence and polarity of the overhang structure is a critical determinant of double-strand break repair pathway choice...
January 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28065797/characterising-the-developmental-profile-of-hesc-derived-medium-spiny-neuron-progenitors-and-assessing-mature-neuron-function-using-a-crispr-generated-human-darpp-32-wt-egfp-amp-reporter-line
#11
C P J Hunt, C W Pouton, J M Haynes
In the developing ventral telencephalon, cells of the lateral ganglionic eminence (LGE) give rise to all medium spiny neurons (MSNs). This development occurs in response to a highly orchestrated series of morphogenetic stimuli that pattern the resultant neurons as they develop. Striatal MSNs are characterised by expression of dopamine receptors, dopamine-and cyclic AMP-regulated phosphoprotein (DARPP32) and the neurotransmitter GABA. In this study, we demonstrate that fine tuning WNT and SHH signaling early in human embryonic stem cell differentiation can induce a subpallial progenitor molecular profile...
January 5, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28054767/orthogonal-genetic-regulation-in-human-cells-using-chemically-induced-crispr-cas9-activators
#12
Zehua Bao, Surbhi Jain, Valerie Jaroenpuntaruk, Huimin Zhao
The concerted action of multiple genes in a time-dependent manner controls complex cellular phenotypes, yet the temporal regulation of gene expressions is restricted on a single gene level, which limits our ability to control higher order gene networks and understand the consequences of multiplexed genetic perturbations. Here we developed a system for temporal regulation of multiple genes. This system combines the simplicity of CRISPR/Cas9 activators for orthogonal targeting of multiple genes and the orthogonality of chemically induced dimerizing (CID) proteins for temporal control of CRISPR/Cas9 activator function...
January 5, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28053351/functional-analysis-of-the-abcs-of-eye-color-in-helicoverpa-armigera-with-crispr-cas9-induced-mutations
#13
Sher Afzal Khan, Michael Reichelt, David G Heckel
Many insect pigments are localized in subcellular pigment granules, and transport of pigment precursors from the cytoplasm is accomplished by ABC proteins. Drosophila melanogaster has three half-transporter genes (white, scarlet, and brown, all affecting eye pigments) and Bombyx mori has a fourth (ok). The White, Brown, Scarlet and Ok proteins each have one transmembrane and one cytoplasmic domain and they heterodimerize to form functional transporters with different substrate specificities. We used CRISPR/Cas9 to create somatic and germ-line knockout mutations of these four genes in the noctuid moth Helicoverpa armigera...
January 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28052104/insertional-mutagenesis-by-crispr-cas9-ribonucleoprotein-gene-editing-in-cells-targeted-for-point-mutation-repair-directed-by-short-single-stranded-dna-oligonucleotides
#14
Natalia Rivera-Torres, Kelly Banas, Pawel Bialk, Kevin M Bloh, Eric B Kmiec
CRISPR/Cas9 and single-stranded DNA oligonucleotides (ssODNs) have been used to direct the repair of a single base mutation in human genes. Here, we examine a method designed to increase the precision of RNA guided genome editing in human cells by utilizing a CRISPR/Cas9 ribonucleoprotein (RNP) complex to initiate DNA cleavage. The RNP is assembled in vitro and induces a double stranded break at a specific site surrounding the mutant base designated for correction by the ssODN. We use an integrated mutant eGFP gene, bearing a single base change rendering the expressed protein nonfunctional, as a single copy target in HCT 116 cells...
2017: PloS One
https://www.readbyqxmd.com/read/28049346/genoproteomics-assisted-improvement-of-andrographis-paniculata-toward-a-promising-molecular-and-conventional-breeding-platform-for-autogamous-plants-affecting-the-pharmaceutical-industry
#15
Alireza Valdiani, Daryush Talei, Surrinder K Lattoo, Rodomiro Ortiz, Søren Kjærsgaard Rasmussen, Jacqueline Batley, Mohd Yusop Rafii, Mahmood Maziah, Kallevettankuzhy K Sabu, Rambod Abiri, Suchirat Sakuanrungsirikul, Soon Guan Tan
Andrographis paniculata (Burm. f.) Wall. ex Nees. (AP) is a hermaphroditic, self-compatible, and habitual inbreeding plant. Its main bioactive component is andrographolide, which is capable of inducing autophagic cell death in some human cancer cells and helps fight HIV/AIDS. Increasing the andrographolide content by investigating the genetic mechanisms controlling its biosynthesis in order to improve and develop high-yielding cultivars are the main breeding targets for AP. However, there might exist some limitations or barriers for crossability within AP accessions...
January 3, 2017: Critical Reviews in Biotechnology
https://www.readbyqxmd.com/read/28049282/crispr-cas9-a-promising-tool-for-gene-editing-on-induced-pluripotent-stem-cells
#16
REVIEW
Eun Ji Kim, Ki Ho Kang, Ji Hyeon Ju
Recent advances in genome editing with programmable nucleases have opened up new avenues for multiple applications, from basic research to clinical therapy. The ease of use of the technology-and particularly clustered regularly interspaced short palindromic repeats (CRISPR)-will allow us to improve our understanding of genomic variation in disease processes via cellular and animal models. Here, we highlight the progress made in correcting gene mutations in monogenic hereditary disorders and discuss various CRISPR-associated applications, such as cancer research, synthetic biology, and gene therapy using induced pluripotent stem cells...
January 2017: Korean Journal of Internal Medicine
https://www.readbyqxmd.com/read/28046023/a-model-to-investigate-single-strand-dna-responses-in-g1-human-cells-via-a-telomere-targeted-nuclease-deficient-crispr-cas9-system
#17
Remco P Crefcoeur, Omar Zgheib, Thanos D Halazonetis
DNA replication stress has the potential to compromise genomic stability and, therefore, cells have developed elaborate mechanisms to detect and resolve problems that may arise during DNA replication. The presence of single-stranded DNA (ssDNA) is often associated with DNA replication stress and serves as a signal for both checkpoint and repair responses. In this study, we exploited a CRISPR-Cas9 system to induce regions of ssDNA in the genome. Specifically, single-guide RNAs bearing sequence complementarity to human telomeric repeats, were used to target nuclease-deficient Cas9 (dCas9) to telomeres...
2017: PloS One
https://www.readbyqxmd.com/read/28038466/drug-dependent-functionalization-of-wild-type-and-mutant-p53-in-cisplatin-resistant-human-ovarian-tumor-cells
#18
Michelle Bhatt, Cristina Ivan, Xiaolei Xie, Zahid H Siddik
Cisplatin (cis-Pt) resistance in tumor cells from p53 dysfunction is a significant clinical problem. Although mutation can inhibit p53 function, >60% of p53 mutants retain normal function according to literature reports. Therefore, we examined the status of p53 in cisplatin-resistant ovarian tumor models and its functional response to cis-Pt and the mechanistically-distinct non-cross-resistant oxaliplatin (oxali-Pt). Relative to sensitive A2780 cells harboring wild-type p53, the 2780CP/Cl-16, OVCAR-10, Hey and OVCA-433 cell lines were 10- to 30-fold resistant to cis-Pt, but was substantially circumvented by oxali-Pt...
December 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/28031181/ibrutinib-inhibits-pre-bcr-b-cell-acute-lymphoblastic-leukemia-progression-by-targeting-btk-and-blk
#19
Ekaterina Kim, Christian Hurtz, Stefan Koehrer, Zhiqiang Wang, Sriram Balasubramanian, Betty Y Chang, Markus Müschen, R Eric Davis, Jan A Burger
Targeting B cell receptor (BCR) signaling is a successful therapeutic strategy in mature B cell malignancies. Precursor BCR (pre-BCR) signaling, which is critical during normal B lymphopoiesis, also plays an important role in pre-BCR(+) B cell acute lymphoblastic leukemia (B-ALL). Here, we investigated the activity and mechanism of action of the BTK inhibitor ibrutinib in preclinical models of B-ALL. Pre-BCR(+) ALL cells were exquisitely sensitive to ibrutinib at therapeutically relevant drug concentrations...
December 28, 2016: Blood
https://www.readbyqxmd.com/read/28027431/from-classical-mutagenesis-to-nuclease-based-breeding-directing-natural-dna-repair-for-a-natural-end-product
#20
Michael Pacher, Holger Puchta
The production of mutants of crop plants by the use of chemical or physical genotoxins has a long tradition. These factors induce the natural DNA repair machinery to repair damages in an error-prone way. In case of radiation, multiple double strand breaks (DSBs) are induced randomly in the genome, leading in very rare cases to a desirable phenotype. In recent years the use of synthetic, site directed nucleases (SDNs), also referred to as sequence specific nucleases (SSNs), like the CRISPR/Cas system, enabled scientists to use exactly the same naturally occurring DNA repair mechanisms for the controlled induction of genomic changes at predefined sites in plant genomes...
December 27, 2016: Plant Journal: for Cell and Molecular Biology
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