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https://www.readbyqxmd.com/read/28525759/modeling-rett-syndrome-using-talen-edited-mecp2-mutant-cynomolgus-monkeys
#1
Yongchang Chen, Juehua Yu, Yuyu Niu, Dongdong Qin, Hailiang Liu, Gang Li, Yingzhou Hu, Jiaojian Wang, Yi Lu, Yu Kang, Yong Jiang, Kunhua Wu, Siguang Li, Jingkuan Wei, Jing He, Junbang Wang, Xiaojing Liu, Yuping Luo, Chenyang Si, Raoxian Bai, Kunshan Zhang, Jie Liu, Shaoyong Huang, Zhenzhen Chen, Shuang Wang, Xiaoying Chen, Xinhua Bao, Qingping Zhang, Fuxing Li, Rui Geng, Aibin Liang, Dinggang Shen, Tianzi Jiang, Xintian Hu, Yuanye Ma, Weizhi Ji, Yi Eve Sun
Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT...
May 18, 2017: Cell
https://www.readbyqxmd.com/read/28524166/homology-mediated-end-joining-based-targeted-integration-using-crispr-cas9
#2
Xuan Yao, Xing Wang, Xinde Hu, Zhen Liu, Junlai Liu, Haibo Zhou, Xiaowen Shen, Yu Wei, Zijian Huang, Wenqin Ying, Yan Wang, Yan-Hong Nie, Chen-Chen Zhang, Sanlan Li, Leping Cheng, Qifang Wang, Yan Wu, Pengyu Huang, Qiang Sun, Linyu Shi, Hui Yang
Targeted integration of transgenes can be achieved by strategies based on homologous recombination (HR), microhomology-mediated end joining (MMEJ) or non-homologous end joining (NHEJ). The more generally used HR is inefficient for achieving gene integration in animal embryos and tissues, because it occurs only during cell division, although MMEJ and NHEJ can elevate the efficiency in some systems. Here we devise a homology-mediated end joining (HMEJ)-based strategy, using CRISPR/Cas9-mediated cleavage of both transgene donor vector that contains guide RNA target sites and ∼800 bp of homology arms, and the targeted genome...
May 19, 2017: Cell Research
https://www.readbyqxmd.com/read/28522548/a-multi-purpose-toolkit-to-enable-advanced-genome-engineering-in-plants
#3
Tomas Cermak, Shaun J Curtin, Javier Gil-Humanes, Radim Čegan, Thomas J Y Kono, Eva Konečná, Joseph J Belanto, Colby G Starker, Jade W Mathre, Rebecca L Greenstein, Daniel F Voytas
We report a comprehensive toolkit that enables targeted, specific modification of monocot and dicot genomes using a variety of genome engineering approaches. Our reagents, based on TALENs and the CRISPR/Cas9 system, are systematized for fast, modular cloning and accommodate diverse regulatory sequences to drive reagent expression. Vectors are optimized to create either single or multiple gene knockouts and large chromosomal deletions. Moreover, integration of geminivirus-based vectors enables precise gene editing through homologous recombination...
May 18, 2017: Plant Cell
https://www.readbyqxmd.com/read/28522326/gene-editing-and-clonal-isolation-of-human-induced-pluripotent-stem-cells-using-crispr-cas9
#4
Saniye Yumlu, Jürgen Stumm, Sanum Bashir, Anne-Kathrin Dreyer, Pawel Lisowski, Eric Danner, Ralf Kühn
Human induced pluripotent stem cells (hiPSCs) represent an ideal in vitro platform to study human genetics and biology. The recent advent of programmable nucleases makes also the human genome amenable to experimental genetics through either the correction of mutations in patient-derived iPSC lines or the de novo introduction of mutations into otherwise healthy iPSCs. The production of specific and sometimes complex genotypes in multiple cell lines requires efficient and streamlined gene editing technologies...
May 15, 2017: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/28521939/developmental-and-evolutionary-mechanisms-shaping-butterfly-eyespots
#5
REVIEW
Patrícia Beldade, Carolina M Peralta
Butterfly eyespots are visually compelling models to study the reciprocal interactions between evolutionary and developmental processes that shape phenotypic variation. They are evolutionarily diversified, ecologically relevant, and developmentally tractable, and have made key contributions to linking genotype, development, phenotype and fitness. Advances in the availability of analytical tools (e.g. gene editing and visualization techniques) and resources (e.g. genomic and transcriptomic data) are boosting the detailed dissection of the mechanisms underlying eyespot development and evolution...
February 2017: Current Opinion in Insect Science
https://www.readbyqxmd.com/read/28521526/the-impact-of-genetics-on-future-drug-discovery-in-schizophrenia
#6
Mitsuyuki Matsumoto, Noah M Walton, Hiroshi Yamada, Yuji Kondo, Gerard J Marek, Katsunori Tajinda
Failures of investigational new drugs (INDs) for schizophrenia have left huge unmet medical needs for patients. Given the recent lackluster results, it is imperative that new drug discovery approaches (and resultant drug candidates) target pathophysiological alterations that are shared in specific, stratified patient populations that are selected based on pre-identified biological signatures. One path to implementing this paradigm is achievable by leveraging recent advances in genetic information and technologies...
May 18, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28515773/building-a-multipurpose-insertional-mutant-library-for-forward-and-reverse-genetics-in-chlamydomonas
#7
Xi Cheng, Gai Liu, Wenting Ke, Lijuan Zhao, Bo Lv, Xiaocui Ma, Nannan Xu, Xiaoling Xia, Xuan Deng, Chunlei Zheng, Kaiyao Huang
BACKGROUND: The unicellular green alga, Chlamydomonas reinhardtii, is a classic model for studying flagella and biofuel. However, precise gene editing, such as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein (Cas9) system, is not widely used in this organism. Screening of random insertional mutant libraries by polymerase chain reaction provides an alternate strategy to obtain null mutants of individual gene. But building, screening, and maintaining such a library was time-consuming and expensive...
2017: Plant Methods
https://www.readbyqxmd.com/read/28514664/lack-of-mttp-activity-in-pluripotent-stem-cell-derived-hepatocytes-and-cardiomyocytes-abolishes-apob-secretion-and-increases-cell-stress
#8
Ying Liu, Donna M Conlon, Xin Bi, Katherine J Slovik, Jianting Shi, Hailey I Edelstein, John S Millar, Ali Javaheri, Marina Cuchel, Evanthia E Pashos, Jahangir Iqbal, M Mahmood Hussain, Robert A Hegele, Wenli Yang, Stephen A Duncan, Daniel J Rader, Edward E Morrisey
Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP(R46G)), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids...
May 16, 2017: Cell Reports
https://www.readbyqxmd.com/read/28514494/covalent-protein-labeling-by-spytag-spycatcher-in-fixed-cells-for-super-resolution-microscopy
#9
Veronica Pessino, Yemima Rose Citron, Siyu Feng, Bo Huang
Labeling proteins with high specificity and efficiency is a fundamental prerequisite for microscopic visualization of subcellular protein structures and interactions. While the comparatively small size of epitope tags makes them less perturbative to fusion proteins, they require the use of large antibodies that often limit probe accessibility and effective resolution. Here we use the covalent SpyTag-SpyCatcher system as an epitope-like tag for fluorescent labeling of intracellular proteins in fixed cells for both conventional and super-resolution microscopy...
May 17, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28513735/highly-efficient-genome-editing-of-human-hematopoietic-stem-cells-via-a-nano-silicon-blade-delivery-approach
#10
Yuan Ma, Xin Han, Oscar Quintana Bustamante, Ricardo Bessa de Castro, Kai Zhang, Pengchao Zhang, Ying Li, Zongbin Liu, Xuewu Liu, Mauro Ferrari, Zhongbo Hu, José Carlos Segovia, Lidong Qin
Recently, the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 bacterial immunity system has opened a promising avenue to treat genetic diseases that affect the human hematopoietic stem cells (HSCs). Therefore, finding a highly efficient delivery method capable of modifying the genome in the hard-to-transfect HSCs, combined with the advanced CRISPR-Cas9 system, may meet the challenges for dissecting the hematologic disease mechanisms and facilitate future clinical applications. Here, we developed an effective HSC-specified delivery microfluidic chip to disrupt the cell membrane transiently by inducing rapid mechanical deformation that allowed the delivery of biomaterials into the cytoplasm from the surrounding matrix...
May 17, 2017: Integrative Biology: Quantitative Biosciences From Nano to Macro
https://www.readbyqxmd.com/read/28512129/mammalian-o-mannosylation-of-cadherins-and-plexins-is-independent-of-protein-o-mannosyltransferase-1-and-2
#11
Ida Signe Bohse Larsen, Yoshiki Narimatsu, Hiren Jitendra Joshi, Zhang Yang, Oliver J Harrison, Julia Brasch, Lawrence Shapiro, Barry Honig, Sergey Y Vakhrushev, Henrik Clausen, Adnan Halim
Protein O-mannosylation is found in yeast and metazoans and a family of conserved orthologous protein O-mannosyltransferases is believed to initiate this important post-translational modification. We recently discovered that the cadherin superfamily carries O-linked mannose (O-Man) glycans at highly conserved residues in specific extracellular cadherin domains, and it was suggested that the function of E-cadherin was dependent on the O-Man glycans. Deficiencies in enzymes catalyzing O-Man biosynthesis, including the two human protein O-mannosyltransferases, POMT1 and POMT2, underlie a subgroup of congenital muscular dystrophies (CMD) designated α-dystroglycanopathies, because deficient O-Man glycosylation of -dystroglycan disrupts laminin interaction with -dystroglycan and the extracellular matrix...
May 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28505980/creation-of-a-novel-humanized-dystrophic-mouse-model-of-duchenne-muscular-dystrophy-and-application-of-a-crispr-cas9-gene-editing-therapy
#12
Courtney S Young, Ekaterina Mokhonova, Marbella Quinonez, April D Pyle, Melissa J Spencer
Duchenne muscular dystrophy is caused by mutations in DMD which disrupt the reading frame. Therapeutic strategies that restore DMD's reading frame, such as exon skipping and CRISPR/Cas9, need to be tested in the context of the human DMD sequence in vivo. We have developed a novel dystrophic mouse model by using CRISPR/Cas9 to delete exon 45 in the human DMD gene in hDMD mice, which places DMD out-of-frame. We have utilized this model to demonstrate that our clinically-relevant CRISPR/Cas9 platform, which targets deletion of human DMD exons 45-55, can be directly applied in vivo to restore dystrophin...
May 6, 2017: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/28504668/hla-e-expressing-pluripotent-stem-cells-escape-allogeneic-responses-and-lysis-by-nk-cells
#13
Germán G Gornalusse, Roli K Hirata, Sarah E Funk, Laura Riolobos, Vanda S Lopes, Gabriel Manske, Donna Prunkard, Aric G Colunga, Laïla-Aïcha Hanafi, Dennis O Clegg, Cameron Turtle, David W Russell
Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this 'missing-self' response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C...
May 15, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28501458/in-vivo-molecular-bioluminescence-imaging-new-tools-and-applications
#14
REVIEW
Laura Mezzanotte, Moniek van 't Root, Hacer Karatas, Elena A Goua, Clemens W G M Löwik
in vivo bioluminescence imaging (BLi) is an optical molecular imaging technique used to visualize molecular and cellular processes in health and diseases and to follow the fate of cells with high sensitivity using luciferase-based gene reporters. The high sensitivity of this technique arises from efficient photon production, followed by the reaction between luciferase enzymes and luciferin substrates. Novel discoveries and developments of luciferase reporters, substrates, and gene-editing techniques, and emerging fields of applications, promise a new era of deeper and more sensitive molecular imaging...
May 10, 2017: Trends in Biotechnology
https://www.readbyqxmd.com/read/28499063/high-efficient-multi-sites-genome-editing-in-allotetraploid-cotton-gossypium-hirsutum-using-crispr-cas9-system
#15
Pengcheng Wang, Jun Zhang, Lin Sun, Yizan Ma, Jiao Xu, Sijia Liang, Jinwu Deng, Jiafu Tan, Qinghua Zhang, Lili Tu, Henry Daniell, Shuangxia Jin, Xianlong Zhang
Gossypium hirsutum is an allotetraploid with a complex genome. Most genes have multiple copies that belong to At and Dt subgenomes. Sequence similarity is also very high between gene homologs. To efficiently achieve site/gene-specific mutation is quite needed. Due to its high efficiency and robustness, the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 system has exerted broad site-specific genome editing from prokaryotes to eukaryotes. In this study, we utilized a CRISPR/Cas9 system to generate two sgRNAs in a single vector to conduct multiple sites genome editing in allotetraploid cotton...
May 12, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/28497073/integrase-deficient-lentiviral-vector-as-an-all-in-one-platform-for-highly-efficient-crispr-cas9-mediated-gene-editing
#16
Pavel I Ortinski, Bernadette O'Donovan, Xiaoyu Dong, Boris Kantor
The CRISPR/Cas9 systems have revolutionized the field of genome editing by providing unprecedented control over gene sequences and gene expression in many species, including humans. Lentiviral vectors (LVs) are one of the primary delivery platforms for the CRISPR/Cas9 system due to their ability to accommodate large DNA payloads and sustain robust expression in a wide range of dividing and non-dividing cells. However, long-term expression of LV-delivered Cas9/guide RNA may lead to undesirable off-target effects characterized by non-specific RNA-DNA interactions and off-target DNA cleavages...
June 16, 2017: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/28492553/a-balance-of-mad-and-myc-expression-dictates-larval-cell-apoptosis-and-adult-stem-cell-development-during-xenopus-intestinal-metamorphosis
#17
Morihiro Okada, Thomas C Miller, Luan Wen, Yun-Bo Shi
The Myc/Mad/Max network has long been shown to be an important factor in regulating cell proliferation, death and differentiation in diverse cell types. In general, Myc-Max heterodimers activate target gene expression to promote cell proliferation, although excess of c-Myc can also induce apoptosis. In contrast, Mad competes against Myc to form Mad-Max heterodimers that bind to the same target genes to repress their expression and promote differentiation. The role of the Myc/Mad/Max network during vertebrate development, especially, the so-called postembryonic development, a period around birth in mammals, is unclear...
May 11, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28489428/a-single-molecule-view-of-genome-editing-proteins-biophysical-mechanisms-for-tales-and-crispr-cas9
#18
Luke Cuculis, Charles M Schroeder
Exciting new advances in genome engineering have unlocked the potential to radically alter the treatment of human disease. In this review, we discuss the application of single-molecule techniques to uncover the mechanisms behind two premier classes of genome editing proteins: transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas). These technologies have facilitated a striking number of gene editing applications in a variety of organisms; however, we are only beginning to understand the molecular mechanisms governing the DNA editing properties of these systems...
May 10, 2017: Annual Review of Chemical and Biomolecular Engineering
https://www.readbyqxmd.com/read/28487425/a-variant-pfcrt-isoform-can-contribute-to-plasmodium-falciparum-resistance-to-the-first-line-partner-drug-piperaquine
#19
Satish K Dhingra, Devasha Redhi, Jill M Combrinck, Tomas Yeo, John Okombo, Philipp P Henrich, Annie N Cowell, Purva Gupta, Matthew L Stegman, Jonathan M Hoke, Roland A Cooper, Elizabeth Winzeler, Sachel Mok, Timothy J Egan, David A Fidock
Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisinin-based combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nuclease-based gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites...
May 9, 2017: MBio
https://www.readbyqxmd.com/read/28481515/sequence-directed-covalent-protein-dna-linkages-in-a-single-step-using-huh-tags
#20
Klaus N Lovendahl, Amanda N Hayward, Wendy Gordon
We present a robust strategy to covalently link proteins and DNA using HUH endonuclease domains as fusion partners (HUH-tags). We show that HUH-tags react robustly with specific sequences of unmodified single-stranded DNA, and have identified five that react orthogonally with distinct DNA sequences. We demonstrate the versatility of HUH-tags as fusion partners in Cas9-mediated gene editing and the construction of doubly DNA-tethered proteins for single molecule studies. Finally we demonstrate application to cellular imaging in live and fixed cells...
May 8, 2017: Journal of the American Chemical Society
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