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Genome editing

Joke Terryn, Tine Tricot, Madhavsai Gajjar, Catherine Verfaillie
Pluripotent stem cells have the property of long-term self-renewal and the potential to give rise to descendants of the three germ layers and hence all mature cells in the human body. Therefore, they hold the promise of offering insight not only into human development but also for human disease modeling and regenerative medicine. However, the generation of mature differentiated cells that closely resemble their in vivo counterparts remains challenging. Recent advances in single-cell transcriptomics and computational modeling of gene regulatory networks are revealing a better understanding of lineage commitment and are driving modern genome editing approaches...
2018: F1000Research
Madiha Kanwal, Xiao-Jie Ding, Xin Song, Guang-Biao Zhou, Yi Cao
Air pollution is one of the leading causes of lung cancer. Air pollution-related lung cancer is a deteriorating public health problem, particularly in developing countries. The MUC16 gene is one of the most frequently mutated genes in air pollution-related lung cancer. In the present study, MUC16 mRNA expression was increased in ∼50% of air pollution-related lung cancer samples obtained from patients residing in air-polluted regions (Xuanwei and Fuyuan, Yunnan, China), and MUC16 mRNA levels were correlated with the degree of air pollution...
February 23, 2018: Oncotarget
Andrew S Fister, Lena Landherr, Siela N Maximova, Mark J Guiltinan
Theobroma cacao , the source of cocoa, suffers significant losses to a variety of pathogens resulting in reduced incomes for millions of farmers in developing countries. Development of disease resistant cacao varieties is an essential strategy to combat this threat, but is limited by sources of genetic resistance and the slow generation time of this tropical tree crop. In this study, we present the first application of genome editing technology in cacao, using Agrobacterium-mediated transient transformation to introduce CRISPR/Cas9 components into cacao leaves and cotyledon cells...
2018: Frontiers in Plant Science
M P L Calus, M E Goddard, Y C J Wientjes, P J Bowman, B J Hayes
Genomic prediction is applicable to individuals of different breeds. Empirical results to date, however, show limited benefits in using information on multiple breeds in the context of genomic prediction. We investigated a multitask Bayesian model, presented previously by others, implemented in a Bayesian stochastic search variable selection (BSSVS) model. This model allowed for evidence of quantitative trait loci (QTL) to be accumulated across breeds or for both QTL that segregate across breeds and breed-specific QTL...
March 14, 2018: Journal of Dairy Science
Yamin Li, Tao Yang, Yingjie Yu, Nicola Shi, Liu Yang, Zachary Glass, Justin Bolinger, Isaac James Finkel, Wenhan Li, Qiaobing Xu
Protein based therapeutics with high specificities and low off-target effects are used for transient and accurate manipulation of cell functions. However, developing safe and efficient carriers for intracellular delivery of active therapeutic proteins is a long-standing challenge. Here we report a combinatorial library of chalcogen (O, S, Se) containing lipidoid nanoparticles (LNPs) as efficient nanocarriers for intracellular delivery of negatively supercharged Cre recombinase ((-30)GFP-Cre) and anionic Cas9:single-guide RNA (Cas9:sgRNA) ribonucleoprotein (RNP) for genome editing...
March 8, 2018: Biomaterials
Richard Sarro, Acadia A Kocher, Deena Emera, Severin Uebbing, Emily V Dutrow, Scott D Weatherbee, Timothy Nottoli, James P Noonan
Developmental gene expression patterns are orchestrated by thousands of distant-acting transcriptional enhancers. However, identifying enhancers essential for the expression of their target genes has proven challenging. Maps of long-range regulatory interactions may provide the means to identify enhancers critical for developmental gene expression. To investigate this hypothesis, we used circular chromosome conformation capture coupled with interaction maps in the mouse limb to characterize the regulatory topology of Pitx1 , which is essential for hindlimb development...
March 16, 2018: Development
Graeme Milligan, Asuka Inoue
Rapid developments in genome editing, based largely on CRISPR/Cas9 technologies, are offering unprecedented opportunities to eliminate the expression of single or multiple gene products in intact organisms and in model cell systems. Elimination of individual G protein-coupled receptors (GPCRs), both single and multiple G protein subunits, and arrestin adaptor proteins is providing new and sometimes unanticipated insights into molecular details of the regulation of cell signalling pathways and the behaviour of receptor ligands...
March 13, 2018: Trends in Pharmacological Sciences
Min Huang, Li Zhu, Jacqueline S Garcia, Michael X Li, Andrew J Gentles, Beverly S Mitchell
We have recently reported that activation of Brd4 is associated with the presence of autophagy in NPMc+ and MLL AML cells. In order to determine the mechanisms underlying this relationship, we have examined the role of Brd4 in regulating the expression of several genes that are central to the process of autophagy. We found that Brd4 binds to the promoters of ATG 3, 7 and CEBPβ, and expression of these genes is markedly reduced by inhibitors of Brd4, as well as by Brd4-shRNA and depletion of CEBPβ. Inhibitors of Brd4 also dramatically suppress the transcription of Keap1, thereby increasing the expression of anti-oxidant genes through the Nrf2 pathway and reducing the cytotoxicity induced by Brd4 inhibitors...
February 20, 2018: Oncotarget
Hong Yang, Jia-Jing Wu, Ting Tang, Ke-De Liu, Cheng Dai
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
March 15, 2018: Scientific Reports
Masato Uchiyama, Akiko Nagai, Kaori Muto
Genome editing of human embryos could become a fundamental treatment approach for genetic diseases; however, a few technical and ethical issues need to be resolved before its application in clinical settings. Presently, the Japanese government has issued a statement prohibiting human germline editing and emphasizing the need for discussions that include a wide range of perspectives. However, current discussions tend to exclude the general public. Therefore, we conducted a survey of 10,881 general adults and 1044 patients in Japan who indicated that their disease conditions are related to their genetic makeup, and clarified their attitude toward this technology...
March 15, 2018: Journal of Human Genetics
Hamid Reza Mirzaei, Hossein Pourghadamyari, Majid Rahmati, Abbas Mohammadi, Javid Sadri Nahand, Abbas Rezaei, Hamed Mirzaei, Jamshid Hadjati
Recently clinical trials utilizing genetically engineered T cells expressing a chimeric antigen receptor (CAR) that is half monoclonal antibody and half T-cell receptor have demonstrated remarkable response in patients with advanced cancers like relapsed or refractory acute lymphoblastic leukemia (ALL) and lymphoma. Moreover, emerging chimeric genome editing tools such as zinc-finger nucleases (ZNFs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas composed of sequence-specific DNA binding module(s) linked to a non-specific DNA cleavage domain have made possible to dramatically expand the ability to manipulate cells aim to treat and/or study a wide range of diseases including cancer...
March 12, 2018: Cancer Letters
Konstantinos C Tsolis, Evridiki-Pandora Tsare, Georgia Orfanoudaki, Tobias Busche, Katerina Kanaki, Reshmi Ramakrishnan, Frederic Rousseau, Joost Schymkowitz, Christian Rückert, Jörn Kalinowski, Jozef Anné, Spyridoula Karamanou, Maria I Klapa, Anastassios Economou
BACKGROUND: Members of the genus Streptomyces are Gram-positive bacteria that are used as important cell factories to produce secondary metabolites and secrete heterologous proteins. They possess some of the largest bacterial genomes and thus proteomes. Understanding their complex proteomes and metabolic regulation will improve any genetic engineering approach. RESULTS: Here, we performed a comprehensive annotation of the subcellular localization of the proteome of Streptomyces lividans TK24 and developed the Subcellular Topology of Polypeptides in Streptomyces database (SToPSdb) to make this information widely accessible...
March 15, 2018: Microbial Cell Factories
Jennifer M Maurer, Charles G Sagerström
BACKGROUND: Signaling cascades, such as the extracellular signal-regulated kinase (ERK) pathway, play vital roles in early vertebrate development. Signals through these pathways are initiated by a growth factor or hormone, are transduced through a kinase cascade, and result in the expression of specific downstream genes that promote cellular proliferation, growth, or differentiation. Tight regulation of these signals is provided by positive or negative modulators at varying levels in the pathway, and is required for proper development and function...
March 15, 2018: BMC Developmental Biology
Suhyung Cho, Donghui Choe, Eunju Lee, Sun Chang Kim, Bernhard Ø Palsson, Byung-Kwan Cho
Along with functional advances in the use of CRISPR/Cas9 for genome editing, endonuclease-deficient Cas9 (dCas9) has provided a versatile molecular tool for exploring gene functions. In principle, differences in cell phenotypes that result from the RNA-guided modulation of transcription levels by dCas9 are critical for inferring with gene function; however, the effect of intracellular dCas9 expression on bacterial morphology has not been systematically elucidated. Here, we observed unexpected morphological changes in Escherichia coli mediated by dCas9, which were then characterized using RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq)...
March 15, 2018: ACS Synthetic Biology
Shashank Gandhi, Florian Razy-Krajka, Lionel Christiaen, Alberto Stolfi
Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 has emerged as a revolutionary tool for fast and efficient targeted gene knockouts and genome editing in almost any organism. The laboratory model tunicate Ciona is no exception. Here, we describe our latest protocol for the design, implementation, and evaluation of successful CRISPR/Cas9-mediated gene knockouts in somatic cells of electroporated Ciona embryos. Using commercially available reagents, publicly accessible plasmids, and free web-based software applications, any Ciona researcher can easily knock out any gene of interest in their favorite embryonic cell lineage...
2018: Advances in Experimental Medicine and Biology
Keita Yoshida, Nicholas Treen
Targeted mutagenesis of genes-of-interest is a powerful method of addressing the functions of genes. Genome editing techniques, such as transcriptional activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 systems, have enabled this approach in various organisms because of their ease of use. In the ascidian, Ciona intestinalis, recent studies show that TALEN-based knockout can be applied to establishing both mutant lines and tissue-specific knockout for addressing gene functions...
2018: Advances in Experimental Medicine and Biology
Mathew A Cherian, Sydney Olson, Hemalatha Sundaramoorthi, Kitra Cates, Xiaogang Cheng, John Harding, Andrew Martens, Grant A Challen, Manoj Tyagi, Lee Ratner, Daniel Rauch
The human T cell leukemia virus-1 (HTLV-1) oncoprotein Tax drives cell proliferation and resistance to apoptosis early in the pathogenesis of adult T-cell leukemia (ATL). Subsequently, likely as a result of specific immuno-editing, Tax expression is downregulated and functionally replaced by somatic driver mutations of the host genome. Both amplification and point mutations of interferon regulatory factor 4 (IRF4) have been previously detected in ATL, and the K59R mutation is the most common single-nucleotide variation in IRF4 and is found exclusively in ATL...
March 14, 2018: Journal of Biological Chemistry
Neftali Vazquez, Lilia Sanchez, Rebecca Marks, Eduardo Martinez, Victor Fanniel, Alma Lopez, Andrea Salinas, Itzel Flores, Jesse Hirschmann, Robert Gilkerson, Erin Schuenzel, Robert Dearth, Reginald Halaby, Wendy Innis-Whitehouse, Megan Keniry
BACKGROUND: Clustered regularly interspaced short palindromic repeat (CRISPR) RNA-guided adaptive immune systems are found in prokaryotes to defend cells from foreign DNA. CRISPR Cas9 systems have been modified and employed as genome editing tools in wide ranging organisms. Here, we provide a detailed protocol to truncate genes in mammalian cells using CRISPR Cas9 editing. We describe custom donor vector construction using Gibson assembly with the commonly utilized pcDNA3 vector as the backbone...
March 14, 2018: BMC Molecular Biology
Eva K Brinkman, Arne N Kousholt, Tim Harmsen, Christ Leemans, Tao Chen, Jos Jonkers, Bas van Steensel
Template-directed CRISPR/Cas9 editing is a powerful tool for introducing subtle mutations in genomes. However, the success rate of incorporation of the desired mutations at the target site is difficult to predict and therefore must be empirically determined. Here, we adapted the widely used TIDE method for quantification of templated editing events, including point mutations. The resulting TIDER method is a rapid, cheap and accessible tool for testing and optimization of template-directed genome editing strategies...
March 10, 2018: Nucleic Acids Research
Magdalena Dabrowska, Wojciech Juzwa, Wlodzimierz J Krzyzosiak, Marta Olejniczak
Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by the expansion of CAG repeats in the first exon of the huntingtin gene ( HTT ). The accumulation of polyglutamine-rich huntingtin proteins affects various cellular functions and causes selective degeneration of neurons in the striatum. Therapeutic strategies used to date to silence the expression of mutant HTT include antisense oligonucleotides, RNA interference-based approaches and, recently, genome editing with the CRISPR/Cas9 system...
2018: Frontiers in Neuroscience
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