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Abhijit Shukla, Danwei Huangfu
Large portions of the human genome harbor functional noncoding elements, which can regulate a variety of biological processes and have important implications for disease risk and therapeutic outcomes. However, assigning specific functions to noncoding sequences remains a major challenge. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein (Cas) systems have emerged as a powerful approach for targeted genome and epigenome perturbation. CRISPR systems are now harnessed for high-throughput screening of the noncoding genome to uncover functional regulatory elements and to define their precise functions with superior speed...
June 15, 2018: Current Opinion in Genetics & Development
Peter J Cowan
The last few years have seen significant progress in xenotransplantation. Porcine xenograft survival in preclinical models continues to improve, accompanied by the adjustment of immunosuppression to more clinically realistic levels. The rapid uptake of CRISPR/Cas9 technology has accelerated the generation of new knock-in and knockout pigs, including animals null for the endogenous retrovirus PERV. This brief review presents a personal view of recent developments in the field.
May 2018: Xenotransplantation
Nicholas Dompe, Christiaan Klijn, Sara A Watson, Katherine Leng, Jenna Port, Trinna Cuellar, Colin Watanabe, Benjamin Haley, Richard Neve, Marie Evangelista, David Stokoe
Mutant KRAS represents one of the most frequently observed oncogenes in NSCLC, yet no therapies are approved for tumors that express activated KRAS variants. While there is strong rationale for the use of MEK inhibitors to treat tumors with activated RAS/MAPK signaling, these have proven ineffective clinically. We therefore implemented a CRISPR screening approach to identify novel agents to sensitize KRAS mutant NSCLC cells to MEK inhibitor treatment. This approach identified multiple components of the canonical RAS/MAPK pathway consistent with previous studies...
2018: PloS One
Ipek Tasan, Gabriela Sustackova, Liguo Zhang, Jiah Kim, Mayandi Sivaguru, Mohammad HamediRad, Yuchuan Wang, Justin Genova, Jian Ma, Andrew S Belmont, Huimin Zhao
Nuclear organization has an important role in determining genome function; however, it is not clear how spatiotemporal organization of the genome relates to functionality. To elucidate this relationship, a method for tracking any locus of interest is desirable. Recently clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) or transcription activator-like effectors were adapted for imaging endogenous loci; however, they are mostly limited to visualization of repetitive regions...
June 15, 2018: Nucleic Acids Research
Juan-José Vasquez, Carolin Wedel, Raul O Cosentino, T Nicolai Siegel
Despite their importance for most DNA-templated processes, the function of individual histone modifications has remained largely unknown because in vivo mutational analyses are lacking. The reason for this is that histone genes are encoded by multigene families and that tools to simultaneously edit multiple genomic loci with high efficiency are only now becoming available. To overcome these challenges, we have taken advantage of the power of CRISPR-Cas9 for precise genome editing and of the fact that most DNA repair in the protozoan parasite Trypanosoma brucei occurs via homologous recombination...
June 15, 2018: Nucleic Acids Research
Cara L Soyars, Brenda A Peterson, Christian A Burr, Zachary L Nimchuk
The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR associated nuclease 9 (Cas9) system is a genome editing technology transforming the field of plant biology by virtue of the system's efficiency and specificity. The system has quickly evolved for many diverse applications including multiplex gene mutation, gene replacement, and transcriptional control. As CRISPR/Cas9 is increasingly applied to plants, it is becoming clear that each component of the system can be modified to improve editing results...
April 18, 2018: Plant & Cell Physiology
Babar Hussain, Stuart James Lucas, Hikmet Budak
The clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) system uses single-guide RNAs for genome editing, making it a simple, robust, powerful tool for targeted gene mutagenesis, knockout and knock-in/replacement, as well as transcriptional regulation. Here, we review the working principles, components and potential modifications of CRISPR/Cas9 for efficient single and multiplex gene editing in plants. We also describe recent work that has used CRISPR/Cas9 to improve economically important traits in crop plants...
April 17, 2018: Briefings in Functional Genomics
Julia B Carleton, Kristofer C Berrett, Jason Gertz
Multiple enhancers often regulate a given gene, yet for most genes, it remains unclear which enhancers are necessary for gene expression, and how these enhancers combine to produce a transcriptional response. As millions of enhancers have been identified, high-throughput tools are needed to determine enhancer function on a genome-wide scale. Current methods for studying enhancer function include making genetic deletions using nuclease-proficient Cas9, but it is difficult to study the combinatorial effects of multiple enhancers using this technique, as multiple successive clonal cell lines must be generated...
June 2, 2018: Journal of Visualized Experiments: JoVE
Shiraz A Shah, Omer S Alkhnbashi, Juliane Behler, Wenyuan Han, Qunxin She, Wolfgang R Hess, Roger A Garrett, Rolf Backofen
A study was undertaken to identify conserved proteins that are encoded adjacent to cas gene cassettes of Type III CRISPR-Cas (Clusters of Regularly IntersSpaced Palindromic Repeats - CRISPR associated) interference modules. Type III modules have been shown to target and degrade dsDNA, ssDNA and ssRNA and are frequently intertwined with cofunctional accessory genes, including genes encoding CRISPR-associated Rossman Fold (CARF) domains. Using a comparative genomics approach, and defining a Type III association score accounting for coevolution and specificity of flanking genes, we identified and classified 39 new Type III associated gene families...
June 18, 2018: RNA Biology
Christoph Paone, Federica Diofano, Deung-Dae Park, Wolfgang Rottbauer, Steffen Just
Cardiovascular disease (CVD) is still the leading cause of death in all western world countries and genetic predisposition in combination with traditional risk factors frequently mediates their manifestation. Genome-wide association (GWA) studies revealed numerous potentially disease modifying genetic loci often including several SNPs and associated genes. However, pure genetic association does not prove direct or indirect relevance of the modifier region on pathogenesis, nor does it define within the associated region the exact genetic driver of the disease...
2018: Frontiers in Cardiovascular Medicine
Cong Wang, Weisheng Cheng, Qian Yu, Tian Xing, Shoubin Chen, Lei Liu, Li Yu, Jian Du, Qingli Luo, Jilong Shen, Yuanhong Xu
Toxoplasma gondii infection evokes a strong Th1-type response with interleukin (IL)-12 and interferon (IFN)-γ secretion. Recent studies suggest that the infection of pregnant mice with T. gondii may lead to adverse pregnancy results caused by subversion of physiological immune tolerance at maternofetal interface rather than direct invasion of the parasite. Genotype-associated dense granule protein GRA15II tends to induce classically activated macrophage (M1) differentiation and subsequently activating NK, Th1, and Th17 cells whereas rhoptry protein ROP16I/III drives macrophages to alternatively activated macrophage (M2) polarization and elicits Th2 immune response...
2018: Frontiers in Immunology
Gang Li, Mengyu Shen, Yuhui Yang, Shuai Le, Ming Li, Jing Wang, Yan Zhao, Yinling Tan, Fuquan Hu, Shuguang Lu
Adaptation of bacteria to phage predation poses a major obstacle for phage therapy. Bacteria adopt multiple mechanisms, such as inhibition of phage adsorption and CRISPR/Cas systems, to resist phage infection. Here, a phage-resistant mutant of Pseudomonas aeruginosa strain PA1 under the infection of lytic phage PaP1 was selected for further study. The PaP1-resistant variant, termed PA1RG, showed decreased adsorption to PaP1 and was devoid of long chain O -antigen on its cell envelope. Whole genome sequencing and comparative analysis revealed a single nucleotide mutation in the gene PA1S_08510, which encodes the O -antigen polymerase Wzy that is involved in lipopolysaccharide (LPS) biosynthesis...
2018: Frontiers in Microbiology
Huihui Sun, Fanfan Li, Jie Liu, Fayu Yang, Zhenhai Zeng, Xiujuan Lv, Mengjun Tu, Yeqing Liu, Xianglian Ge, Changbao Liu, Junzhao Zhao, Zongduan Zhang, Jia Qu, Zongming Song, Feng Gu
Cpf1 has been harnessed as a tool for genome manipulation in various species because of its simplicity and high efficiency. Our recent study demonstrated that FnCpf1 could be utilized for human genome editing with notable advantages for target sequence selection due to the flexibility of the protospacer adjacent motif (PAM) sequence. Multiplex genome editing provides a powerful tool for targeting members of multigene families, dissecting gene networks, modeling multigenic disorders in vivo, and applying gene therapy...
June 15, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Rasmus O Bak, Natalia Gomez-Ospina, Matthew H Porteus
Smithies et al. (1985) and Jasin and colleagues (1994) provided proof of concept that homologous recombination (HR) could be applied to the treatment of human disease and that its efficiency could be improved by the induction of double-strand breaks (DSBs). A key advance was the discovery of engineered nucleases, such as zinc-finger nucleases (ZFNs) and transcription activator-like (TAL) effector nucleases (TALENs), that can generate site-specific DSBs. The democratization and widespread use of genome editing was enabled by the discovery of the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease system...
June 13, 2018: Trends in Genetics: TIG
Takahiro Ohde, Yusuke Takehana, Takahiro Shiotsuki, Teruyuki Niimi
Despite previous developmental studies on basally branching wingless insects and crustaceans, the evolutionary origin of insect wings remains controversial. Knowledge regarding genetic regulation of tissues hypothesized to have given rise to wings would help to elucidate how ancestral development changed to allow the evolution of true wings. However, genetic tools available for basally branching wingless species are limited. The firebrat Thermobia domestica is an apterygote species, phylogenetically related to winged insects...
June 13, 2018: Arthropod Structure & Development
Waqas Muhammad Usman, Tin Chanh Pham, Yuk Yan Kwok, Luyen Tien Vu, Victor Ma, Boya Peng, Yuen San Chan, Likun Wei, Siew Mei Chin, Ajijur Azad, Alex Bai-Liang He, Anskar Y H Leung, Mengsu Yang, Ng Shyh-Chang, William C Cho, Jiahai Shi, Minh T N Le
Most of the current methods for programmable RNA drug therapies are unsuitable for the clinic due to low uptake efficiency and high cytotoxicity. Extracellular vesicles (EVs) could solve these problems because they represent a natural mode of intercellular communication. However, current cellular sources for EV production are limited in availability and safety in terms of horizontal gene transfer. One potentially ideal source could be human red blood cells (RBCs). Group O-RBCs can be used as universal donors for large-scale EV production since they are readily available in blood banks and they are devoid of DNA...
June 15, 2018: Nature Communications
Suji Hong, Donghyun Ka, Seo Jeong Yoon, Nayoung Suh, Migyeong Jeong, Jeong-Yong Suh, Euiyoung Bae
No abstract text is available yet for this article.
June 15, 2018: Journal of Biological Chemistry
Agnieszka A Piatek, Scott C Lenaghan, C Neal Stewart
Genome editing is a powerful suite of technologies utilized in basic and applied plant research. Both nuclear and plastid genomes have been genetically engineered to alter traits in plants. While the most frequent molecular outcome of gene editing has been knockouts resulting in a simple deletion of an endogenous protein of interest from the host's proteome, new genes have been added to plant genomes and, in several instances, the sequence of endogenous genes have been targeted for a few coding changes. Targeted plant characteristics for genome editing range from single gene targets for agronomic input traits to metabolic pathways to endow novel plant function...
August 2018: Plant Science: An International Journal of Experimental Plant Biology
Benjamin M Woolston, David F Emerson, Devin H Currie, Gregory Stephanopoulos
Clostridium ljungdahlii has emerged as an attractive candidate for the bioconversion of synthesis gas (CO, CO2 , H2 ) to a variety of fuels and chemicals through the Wood-Ljungdahl pathway. However, metabolic engineering and pathway elucidation in this microbe is limited by the lack of genetic tools to downregulate target genes. To overcome this obstacle, here we developed an inducible CRISPR interference (CRISPRi) system for C. ljungdahlii that enables efficient (>94%) transcriptional repression of several target genes, both individually and in tandem...
June 12, 2018: Metabolic Engineering
(no author information available yet)
No abstract text is available yet for this article.
June 14, 2018: Cell
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