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CRISPR CAS9 human

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https://www.readbyqxmd.com/read/29044507/tieg-and-estrogen-modulate-sost-expression-in-the-murine-skeleton
#1
Malayannan Subramaniam, Kevin S Pitel, Elizabeth S Bruinsma, David G Monroe, John R Hawse
TIEG knockout (KO) mice exhibit a female-specific osteopenic phenotype and altered expression of TIEG in humans is associated with osteoporosis. Gene expression profiling studies identified sclerostin as one of the most highly up-regulated transcripts in the long bones of TIEG KO mice relative to WT littermates suggesting that TIEG may regulate SOST expression. TIEG was shown to substantially suppress SOST promoter activity and the regulatory elements through which TIEG functions were identified using promoter deletion and chromatin immunoprecipitation assays...
October 16, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29042501/plasmodium-falciparum-calcium-dependent-protein-kinase-2-is-critical-for-male-gametocyte-exflagellation-but-not-essential-for-asexual-proliferation
#2
Abhisheka Bansal, Alvaro Molina-Cruz, Joseph Brzostowski, Jianbing Mu, Louis H Miller
Drug development efforts have focused mostly on the asexual blood stages of the malaria parasite Plasmodium falciparum Except for primaquine, which has its own limitations, there are no available drugs that target the transmission of the parasite to mosquitoes. Therefore, there is a need to validate new parasite proteins that can be targeted for blocking transmission. P. falciparum calcium-dependent protein kinases (PfCDPKs) play critical roles at various stages of the parasite life cycle and, importantly, are absent in the human host...
October 17, 2017: MBio
https://www.readbyqxmd.com/read/29040522/behavioral-and-transcriptomic-analysis-of-trem2-null-mice-not-all-knockout-mice-are-created-equal
#3
Silvia S Kang, Aishe Kurti, Kelsey E Baker, Chia-Chen Liu, Marco Colonna, Jason D Ulrich, David M Holtzman, Guojun Bu, John D Fryer
It is clear that innate immune system status is altered in numerous neurodegenerative diseases. Human genetic studies have demonstrated that Triggering Receptor Expressed in Myeloid cells 2 (TREM2) coding variants have a strong association with Alzheimer's disease (AD) and other neurodegenerative diseases. To more thoroughly understand the impact of TREM2 in vivo, we studied the behavioral and cognitive functions of wild-type (WT) and Trem2-/- (KO) mice during basal conditions and brain function in the context of innate immune stimulation with peripherally administered lipopolysaccharide (LPS)...
October 11, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29038945/human-germline-editing-a-historical-perspective
#4
Michel Morange
The development of the genome editing system called CRISPR-Cas9 has opened a huge debate on the possibility of modifying the human germline. But the types of changes that could and/or ought to be made have not been discussed. To cast some light on this debate, I will describe the story of the CRISPR-Cas9 system. Then, I will briefly review the projects for modification of the human species that were discussed by biologists throughout the twentieth century. Lastly, I will show that for plenty of reasons, both scientific and societal, germline modification is no longer a priority for our societies...
October 16, 2017: History and Philosophy of the Life Sciences
https://www.readbyqxmd.com/read/29038160/a-high-resolution-genome-wide-crispr-cas9-viability-screen-reveals-structural-features-and-contextual-diversity-of-the-human-cell-essential-proteome
#5
Thierry Bertomeu, Jasmin Coulombe-Huntington, Andrew Chatr-Aryamontri, Karine Bourdages, Etienne Coyaud, Brian Raught, Yu Xia, Mike Tyers
To interrogate genes essential for cell growth, proliferation and survival in human cells, we carried out a genome-wide CRISPR/Cas9 screen in a B-cell lymphoma line using a custom extended knockout (EKO) library of 278,754 sgRNAs that targeted 19,084 RefSeq genes, 20,852 alternatively-spliced exons and 3,872 hypothetical genes. A new statistical analysis tool called RANKS identified 2,280 essential genes, 234 of which were unique. Individual essential genes were validated experimentally and linked to ribosome biogenesis and stress responses...
October 16, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29036432/copb2-is-essential-for-embryogenesis-and-hypomorphic-mutations-cause-human-microcephaly
#6
Andrew DiStasio, Ashley Driver, Kristen Sund, Milene Donlin, Ranjith M Muraleedharan, Shabnam Pooya, Beth Kline-Fath, Kenneth M Kaufman, Cynthia A Prows, Elizabeth Schorry, Biplab DasGupta, Rolf W Stottmann
Primary microcephaly is a congenital brain malformation characterized by a head circumference less than three standard deviations below the mean for age and sex and results in moderate to severe mental deficiencies and decreased lifespan. We recently studied two children with primary microcephaly in an otherwise unaffected family. Exome sequencing identified an autosomal recessive mutation leading to an amino acid substitution in a WD40 domain of the highly conserved Coatomer Protein Complex, Subunit Beta 2 (COPB2)...
September 19, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29035510/crispri-and-crispra-screens-in-mammalian-cells-for-precision-biology-and-medicine
#7
Martin Kampmann
Next-generation DNA sequencing technologies have led to a massive accumulation of genomic and transcriptomic data from patients and healthy individuals. The major challenge ahead is to understand the functional significance of the elements of the human genome and transcriptome, and implications for diagnosis and treatment. Genetic screens in mammalian cells are a powerful approach to systematically elucidate gene function in health and disease states. In particular, recently developed CRISPR/Cas9-based screening approaches have enormous potential to uncover mechanisms and therapeutic strategies for human diseases...
October 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29034901/generation-of-a-kcnj11-homozygous-knockout-human-embryonic-stem-cell-line-wae001-a-12-using-crispr-cas9
#8
Fang Yuan, Dongsheng Guo, Ge Gao, Yanli Liu, Yingying Xu, Yuhang Wu, Fan Yang, Xinrong Ke, Keyu Lai, Liangqing Hong, Yin-Xiong Li
The ATP-sensitive potassium channel is an octameric complex, and one of its subunits, namely Kir6.2, is encoded by the KCNJ11 gene. Mutations in KCNJ11 result in hyperinsulinism or diabetes mellitus, associated with abnormal insulin secretion. Here, using CRISPR/Cas9 editing, we established a homozygous mutant KCNJ11 cell line, WAe001-A-12, which was generated by a 62-bp deletion in the coding sequence of the human embryonic stem cell line H1. It was confirmed that this deletion in the KCNJ11 gene did not affect the protein expression levels of key pluripotent factors...
October 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29034888/generation-of-two-men1-knockout-lines-from-a-human-embryonic-stem-cell-line
#9
Yanli Liu, Aynisahan Ruzi, Dongsheng Guo, Feima Wu, Haikun Liu, Han Wu, Yuhang Wu, Fang Yuan, Yuanqi Zhuang, Fan Yang, Keyu Lai, Liangxue Lai, Yin-Xiong Li
The MEN1 gene is cytogenetically located at 11q13.1 and encodes the nuclear protein menin, which is involved in cell proliferation, apoptosis, differentiation, and metabolism. Here, we generated two MEN1 knockout human embryonic stem cell lines, WAe001-A-4 and WAe001-A-5, by targeting exon-2 and exon-9 of MEN1 using the CRISPR/Cas9 technique. These cell lines maintained their pluripotency, in vitro differentiation potential, normal morphology, and karyotype. These human MEN1-mutated cell lines not only enlarge the pool of lab resources but also provide ideal models to dissect the detailed physio-pathological roles of the menin protein...
October 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29034887/generation-of-three-mir-122-knockout-lines-from-a-human-embryonic-stem-cell-line
#10
Yanli Liu, Feima Wu, Yuanqi Zhuang, Dongsheng Guo, Nasir Abbas, Ruzi Wei, Kepin Wang, Yan Chen, Jiawang Tao, Yuhang Wu, Fang Yuan, Tingcai Pan, Fan Yang, Keyu Lai, Liangxue Lai, Yin-Xiong Li
miR-122 is the most abundant miRNA in the human liver, accounting for 52% of the entire hepatic miRNome. Previous studies have demonstrated that miR-122 plays key roles in hepatocyte growth, metabolism, and homeostasis. Here, we created three miR-122 knockout human embryonic stem cell line lines, WAe001-A-7, WAe001-A-8, and WAe001-A-9, using the CRISPR/Cas9 technique. These mutated cell lines retained their pluripotency, in vitro differentiation potential, normal morphology, and karyotype.
October 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29034883/establishment-of-a-congenital-tooth-agenesis-related-gene-msx1-knockout-human-embryonic-stem-cell-lines-by-crispr-cas9-technology
#11
Yanting Xue, Minghui Zhu, Dajiang Qin, Yongjin Li, Xiaotong Cen, Xiaofang Sun, Wenwei Lian, Baojian Liao
Human MSX1 gene is mapped to chromosome 4 and encodes a 303aa homeobox protein MSX1. MSX1 expression appears during early tooth development of vertebrate embryogenesis. Mutations in this protein are related to human tooth anomalie, cleft lip and palate and congenital ectodermal dysplasia syndrome. Most of the confirmed pathogenic mutations are located in exon2 encoded homeobox domain. Here, we report the establishment of MSX1 gene knockout human embryonic stem (hES) cell lines by CRISPR-Cas9 technology. These cell lines provide good materials for further studies of the roles MSX1 plays in human tooth development and congenital tooth agenesis...
October 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29028415/crispr-cas9-mediated-noncoding-rna-editing-in-human-cancers
#12
Jie Yang, Xiaodan Meng, Jinchang Pan, Nan Jiang, Chengwei Zhou, Zhenhua Wu, Zhaohui Gong
Cancer is characterized by multiple genetic and epigenetic alterations, including a higher prevalence of mutations of oncogenes and/or tumor suppressors. Mounting evidences have shown that noncoding RNAs (ncRNAs) are involved in the epigenetic regulation of cancer genes and their associated pathways. The clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease 9 (CRISPR/Cas9) system, a revolutionary genome-editing technology, has shed light on ncRNA-based cancer therapy. Here, we briefly introduce the classifications and mechanisms of CRISPR/Cas9 system...
October 13, 2017: RNA Biology
https://www.readbyqxmd.com/read/29025896/high-throughput-single-molecule-telomere-characterization
#13
Jennifer McCaffrey, Eleanor Young, Katy Lassahn, Justin Sibert, Steven Pastor, Harold Riethman, Ming Xiao
We have developed a novel method that enables global subtelomere and haplotype-resolved analysis of telomere lengths at the single-molecule level. An in vitro CRISPR/Cas9 RNA-directed nickase system directs the specific labeling of human (TTAGGG)n DNA tracts in genomes that have also been barcoded using a separate nickase enzyme that recognizes a 7-bp motif genome-wide. High-throughput imaging and analysis of large DNA single molecules from genomes labeled in this fashion using a nanochannel array system permits mapping through subtelomere repeat element (SRE) regions to unique chromosomal DNA while simultaneously measuring the (TTAGGG)n tract length at the end of each large telomere-terminal DNA segment...
October 12, 2017: Genome Research
https://www.readbyqxmd.com/read/29024560/enhanced-stem-cell-differentiation-and-immunopurification-of-genome-engineered-human-retinal-ganglion-cells
#14
Valentin M Sluch, Xitiz Chamling, Melissa M Liu, Cynthia A Berlinicke, Jie Cheng, Katherine L Mitchell, Derek S Welsbie, Donald J Zack
Human pluripotent stem cells have the potential to promote biological studies and accelerate drug discovery efforts by making possible direct experimentation on a variety of human cell types of interest. However, stem cell cultures are generally heterogeneous and efficient differentiation and purification protocols are often lacking. Here, we describe the generation of clustered regularly-interspaced short palindromic repeats(CRISPR)-Cas9 engineered reporter knock-in embryonic stem cell lines in which tdTomato and a unique cell-surface protein, THY1...
October 10, 2017: Stem Cells Translational Medicine
https://www.readbyqxmd.com/read/29023819/non-alcoholic-fatty-liver-disease-impairs-expression-of-the-type-ii-inositol-1-4-5-trisphosphate-receptor
#15
Tanaporn Khamphaya, Natsasi Chukijrungroat, Vitoon Saengsirisuwan, Kisha A Mitchell-Richards, Marie E Robert, Albert Mennone, Michael H Nathanson, Jittima Weerachayaphorn
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide. It may result in several types of liver problems including impaired liver regeneration, but the mechanism for this is unknown. Because liver regeneration depends on calcium signaling, we examined the effects of NAFLD on expression of the type II inositol 1,4,5-trisphosphate receptor (ITPR2), the principle calcium release channel in hepatocytes. ITPR2 promoter activity was measured in Huh7 and HepG2 cells. ITPR2 and c-Jun protein levels were evaluated in Huh7 cells, in liver tissue from a rat model of NAFLD and in liver biopsy specimens of patients with simple steatosis and non-alcoholic steatohepatitis (NASH)...
October 10, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29021520/hdac6-inhibition-reverses-axonal-transport-defects-in-motor-neurons-derived-from-fus-als-patients
#16
Wenting Guo, Maximilian Naujock, Laura Fumagalli, Tijs Vandoorne, Pieter Baatsen, Ruben Boon, Laura Ordov√°s, Abdulsamie Patel, Marc Welters, Thomas Vanwelden, Natasja Geens, Tine Tricot, Veronick Benoy, Jolien Steyaert, Cynthia Lefebvre-Omar, Werend Boesmans, Matthew Jarpe, Jared Sterneckert, Florian Wegner, Susanne Petri, Delphine Bohl, Pieter Vanden Berghe, Wim Robberecht, Philip Van Damme, Catherine Verfaillie, Ludo Van Den Bosch
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder due to selective loss of motor neurons (MNs). Mutations in the fused in sarcoma (FUS) gene can cause both juvenile and late onset ALS. We generated and characterized induced pluripotent stem cells (iPSCs) from ALS patients with different FUS mutations, as well as from healthy controls. Patient-derived MNs show typical cytoplasmic FUS pathology, hypoexcitability, as well as progressive axonal transport defects. Axonal transport defects are rescued by CRISPR/Cas9-mediated genetic correction of the FUS mutation in patient-derived iPSCs...
October 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/29021165/preclinical-modeling-highlights-the-therapeutic-potential-of-hematopoietic-stem-cell-gene-editing-for-correction-of-scid-x1
#17
Giulia Schiroli, Samuele Ferrari, Anthony Conway, Aurelien Jacob, Valentina Capo, Luisa Albano, Tiziana Plati, Maria C Castiello, Francesca Sanvito, Andrew R Gennery, Chiara Bovolenta, Rahul Palchaudhuri, David T Scadden, Michael C Holmes, Anna Villa, Giovanni Sitia, Angelo Lombardo, Pietro Genovese, Luigi Naldini
Targeted genome editing in hematopoietic stem/progenitor cells (HSPCs) is an attractive strategy for treating immunohematological diseases. However, the limited efficiency of homology-directed editing in primitive HSPCs constrains the yield of corrected cells and might affect the feasibility and safety of clinical translation. These concerns need to be addressed in stringent preclinical models and overcome by developing more efficient editing methods. We generated a humanized X-linked severe combined immunodeficiency (SCID-X1) mouse model and evaluated the efficacy and safety of hematopoietic reconstitution from limited input of functional HSPCs, establishing thresholds for full correction upon different types of conditioning...
October 11, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29020615/a-scaled-framework-for-crispr-editing-of-human-pluripotent-stem-cells-to-study-psychiatric-disease
#18
Dane Z Hazelbaker, Amanda Beccard, Anne M Bara, Nicole Dabkowski, Angelica Messana, Patrizia Mazzucato, Daisy Lam, Danielle Manning, Kevin Eggan, Lindy E Barrett
Scaling of CRISPR-Cas9 technology in human pluripotent stem cells (hPSCs) represents an important step for modeling complex disease and developing drug screens in human cells. However, variables affecting the scaling efficiency of gene editing in hPSCs remain poorly understood. Here, we report a standardized CRISPR-Cas9 approach, with robust benchmarking at each step, to successfully target and genotype a set of psychiatric disease-implicated genes in hPSCs and provide a resource of edited hPSC lines for six of these genes...
October 10, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29019352/hot-news-gene-therapy-with-crispr-cas9-coming-to-age-for-hiv-cure
#19
Vicente Soriano
The huge success of current antiretroviral therapy is mediated by a triple effect: (i) Halting progression to AIDS in infected persons; (ii) reducing the risk of transmission to contacts (treatment as prevention); and (iii) minimizing the risk of HIV acquisition treating uninfected persons at risk (pre-exposure prophylaxis). However, UNAIDS has estimated that only 70% of infected people globally are diagnosed, only 53% are treated, and overall 44% have undetectable viral load, which is the necessary request for ensuring any antiretroviral benefit...
October 11, 2017: AIDS Reviews
https://www.readbyqxmd.com/read/29017167/hopes-and-difficulties-for-blastocyst-complementation
#20
Benjamin S Freedman
The clinical need for organ replacement therapies has inspired the idea of growing human organs in animal hosts. The injection of human pluripotent stem cells into animal blastocysts provides a possible strategy to accomplish this goal. Subject of Review: A recent study [Wu et al. Cell 2017;168:473-486.e415] tests the feasibility of this approach by creating chimeric embryos between humans and large domestic animals, including pigs and cattle. The study further examines the potential of combining CRISPR-Cas9 gene editing with blastocyst complementation to grow fully foreign organs in chimeric hosts...
October 10, 2017: Nephron
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