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Genome Editing human

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https://www.readbyqxmd.com/read/29048557/linkage-of-a-to-i-rna-editing-in-metazoans-and-the-impact-on-genome-evolution
#1
Yuange Duan, Shengqian Dou, Hong Zhang, Changcheng Wu, Mingming Wu, Jian Lu
The adenosine-to-inosine (A-to-I) RNA editomes have been systematically characterized in various metazoan species, and many editing sites were found in clusters. However, it remains unclear whether the clustered editing sites tend to be linked in the same RNA molecules or not. By adopting a method originally designed to detect linkage disequilibrium of DNA mutations, we examined the editomes of ten metazoan species and detected extensive linkage of editing in Drosophila and cephalopods. The prevalent linkages of editing in these two clades, many of which are conserved between closely related species and might be associated with the adaptive proteomic recoding, are maintained by natural selection at the cost of genome evolution...
October 18, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/29040648/molecular-basis-for-asymmetry-sensing-of-sirnas-by-the-drosophila-loqs-pd-dcr-2-complex-in-rna-interference
#2
Jan-Niklas Tants, Stephanie Fesser, Thomas Kern, Ralf Stehle, Arie Geerlof, Christoph Wunderlich, Michael Juen, Christoph Hartlmüller, Romy Böttcher, Stefan Kunzelmann, Oliver Lange, Christoph Kreutz, Klaus Förstemann, Michael Sattler
RNA interference defends against RNA viruses and retro-elements within an organism's genome. It is triggered by duplex siRNAs, of which one strand is selected to confer sequence-specificity to the RNA induced silencing complex (RISC). In Drosophila, Dicer-2 (Dcr-2) and the double-stranded RNA binding domain (dsRBD) protein R2D2 form the RISC loading complex (RLC) and select one strand of exogenous siRNAs according to the relative thermodynamic stability of base-pairing at either end. Through genome editing we demonstrate that Loqs-PD, the Drosophila homolog of human TAR RNA binding protein (TRBP) and a paralog of R2D2, forms an alternative RLC with Dcr-2 that is required for strand choice of endogenous siRNAs in S2 cells...
October 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29038945/human-germline-editing-a-historical-perspective
#3
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/29036432/copb2-is-essential-for-embryogenesis-and-hypomorphic-mutations-cause-human-microcephaly
#4
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/29032169/survival-advantage-of-both-human-hepatocyte-xenografts-and-genome-edited-hepatocytes-for-treatment-of-%C3%AE-1-antitrypsin-deficiency
#5
Florie Borel, Qiushi Tang, Gwladys Gernoux, Cynthia Greer, Ziqiong Wang, Adi Barzel, Mark A Kay, Leonard D Shultz, Dale L Greiner, Terence R Flotte, Michael A Brehm, Christian Mueller
Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In α-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver...
September 25, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29029851/arresting-evolution
#6
REVIEW
James J Bull, Jeffrey E Barrick
Evolution in the form of selective breeding has long been harnessed as a useful tool by humans. However, rapid evolution can also be a danger to our health and a stumbling block for biotechnology. Unwanted evolution can underlie the emergence of drug and pesticide resistance, cancer, and weeds. It makes live vaccines and engineered cells inherently unreliable and unpredictable, and therefore potentially unsafe. Yet, there are strategies that have been and can possibly be used to stop or slow many types of evolution...
October 10, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/29028415/crispr-cas9-mediated-noncoding-rna-editing-in-human-cancers
#7
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/29022589/dynamic-landscape-and-regulation-of-rna-editing-in-mammals
#8
Meng How Tan, Qin Li, Raghuvaran Shanmugam, Robert Piskol, Jennefer Kohler, Amy N Young, Kaiwen Ivy Liu, Rui Zhang, Gokul Ramaswami, Kentaro Ariyoshi, Ankita Gupte, Liam P Keegan, Cyril X George, Avinash Ramu, Ni Huang, Elizabeth A Pollina, Dena S Leeman, Alessandra Rustighi, Y P Sharon Goh, Ajay Chawla, Giannino Del Sal, Gary Peltz, Anne Brunet, Donald F Conrad, Charles E Samuel, Mary A O'Connell, Carl R Walkley, Kazuko Nishikura, Jin Billy Li
Adenosine-to-inosine (A-to-I) RNA editing is a conserved post-transcriptional mechanism mediated by ADAR enzymes that diversifies the transcriptome by altering selected nucleotides in RNA molecules. Although many editing sites have recently been discovered, the extent to which most sites are edited and how the editing is regulated in different biological contexts are not fully understood. Here we report dynamic spatiotemporal patterns and new regulators of RNA editing, discovered through an extensive profiling of A-to-I RNA editing in 8,551 human samples (representing 53 body sites from 552 individuals) from the Genotype-Tissue Expression (GTEx) project and in hundreds of other primate and mouse samples...
October 11, 2017: Nature
https://www.readbyqxmd.com/read/29021890/zebrafish-knockout-of-down-syndrome-gene-dyrk1a-shows-social-impairments-relevant-to-autism
#9
Oc-Hee Kim, Hyun-Ju Cho, Enna Han, Ted Inpyo Hong, Krishan Ariyasiri, Jung-Hwa Choi, Kyu-Seok Hwang, Yun-Mi Jeong, Se-Yeol Yang, Kweon Yu, Doo-Sang Park, Hyun-Woo Oh, Erica E Davis, Charles E Schwartz, Jeong-Soo Lee, Hyung-Goo Kim, Cheol-Hee Kim
BACKGROUND: DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism...
2017: Molecular Autism
https://www.readbyqxmd.com/read/29021165/preclinical-modeling-highlights-the-therapeutic-potential-of-hematopoietic-stem-cell-gene-editing-for-correction-of-scid-x1
#10
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
#11
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
#12
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/28993641/revealing-hidden-complexities-of-genomic-rearrangements-generated-with-cas9
#13
Katharina Boroviak, Beiyuan Fu, Fengtang Yang, Brendan Doe, Allan Bradley
Modelling human diseases caused by large genomic rearrangements has become more accessible since the utilization of CRISPR/Cas9 in mammalian systems. In a previous study, we showed that genomic rearrangements of up to one million base pairs can be generated by direct injection of CRISPR/Cas9 reagents into mouse zygotes. Although these rearrangements are ascertained by junction PCR, we describe here a variety of anticipated structural changes often involving reintegration of the region demarcated by the gRNAs in the vicinity of the edited locus...
October 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28992411/genome-editing-insights-from-chemical-biology-to-support-safe-and-transformative-therapeutic-applications
#14
Renee D Wegrzyn, Andrew H Lee, Amy L Jenkins, Colby D Stoddard, Anne E Cheever
Programmable nuclease-based genome editing technologies, including the clustered, regularly interspaced, short palindromic repeats (CRISPR)/Cas9 system, are becoming an essential component of many applications ranging from agriculture to medicine. However, fundamental limitations including the potential for off-target effects, limited control of editing activity and subsequent DNA repair outcomes, and insufficient target conversion and delivery performance prevent the widespread, safe, and practical use of genome editors, especially for human disease interventions...
October 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28988985/facs-assisted-crispr-cas9-genome-editing-facilitates-parkinson-s-disease-modeling
#15
Jonathan Arias-Fuenzalida, Javier Jarazo, Xiaobing Qing, Jonas Walter, Gemma Gomez-Giro, Sarah Louise Nickels, Holm Zaehres, Hans Robert Schöler, Jens Christian Schwamborn
Genome editing and human induced pluripotent stem cells hold great promise for the development of isogenic disease models and the correction of disease-associated mutations for isogenic tissue therapy. CRISPR-Cas9 has emerged as a versatile and simple tool for engineering human cells for such purposes. However, the current protocols to derive genome-edited lines require the screening of a great number of clones to obtain one free of random integration or on-locus non-homologous end joining (NHEJ)-containing alleles...
September 26, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28988714/genome-wide-mapping-of-off-target-events-in-single-stranded-oligodeoxynucleotide-mediated-gene-repair-experiments
#16
Sarah Radecke, Klaus Schwarz, Frank Radecke
Short single-stranded oligodeoxynucleotides are versatile molecular tools used in different applications. They enable gene repair and genome editing, and they are central to the antisense technology. Because the usability of single-stranded oligodeoxynucleotides depends on their efficiencies, as well as their specificities, analyzing their genotoxic off-target activities is important. Thus, we have developed a protocol that follows the fate of a biotin-labeled single-stranded oligodeoxynucleotide in human cells based on its physical incorporation into the targeted genome...
September 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28986802/re-expressing-epigenetically-silenced-genes-by-inducing-dna-demethylation-through-targeting-of-ten-eleven-translocation-2-to-any-given-genomic-locus
#17
Julio Cesar Rendón, David Cano-Rodríguez, Marianne G Rots
Epigenetic editing is a novel methodology to modify the epigenetic landscape of any genomic location. As such, the approach might reprogram expression profiles, without altering the DNA sequence. Epigenetic alterations, including promoter hypermethylation, are associated with an increasing number of human diseases. To exploit this situation, epigenetic editing rises as a new alternative to specifically demethylate abnormally hypermethylated regions. Here, we describe a methodology to actively demethylate the hypermethylated ICAM-1 promoter...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28986351/the-council-of-europe-should-not-reaffirm-the-ban-on-germline-genome-editing-in-humans
#18
Peter Sykora, Arthur Caplan
No abstract text is available yet for this article.
October 6, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28985529/multiplex-crispr-cas9-based-genome-editing-in-human-hematopoietic-stem-cells-models-clonal-hematopoiesis-and-myeloid-neoplasia
#19
Zuzana Tothova, John M Krill-Burger, Katerina D Popova, Catherine C Landers, Quinlan L Sievers, David Yudovich, Roger Belizaire, Jon C Aster, Elizabeth A Morgan, Aviad Tsherniak, Benjamin L Ebert
Hematologic malignancies are driven by combinations of genetic lesions that have been difficult to model in human cells. We used CRISPR/Cas9 genome engineering of primary adult and umbilical cord blood CD34(+) human hematopoietic stem and progenitor cells (HSPCs), the cells of origin for myeloid pre-malignant and malignant diseases, followed by transplantation into immunodeficient mice to generate genetic models of clonal hematopoiesis and neoplasia. Human hematopoietic cells bearing mutations in combinations of genes, including cohesin complex genes, observed in myeloid malignancies generated immunophenotypically defined neoplastic clones capable of long-term, multi-lineage reconstitution and serial transplantation...
October 5, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28985524/human-genome-editing-in-the-clinic-new-challenges-in-regulatory-benefit-risk-assessment
#20
Mohamed Abou-El-Enein, Toni Cathomen, Zoltán Ivics, Carl H June, Matthias Renner, Christian K Schneider, Gerhard Bauer
As genome editing rapidly progresses toward the realization of its clinical promise, assessing the suitability of current tools and processes used for its benefit-risk assessment is critical. Although current regulations may initially provide an adequate regulatory framework, improvements are recommended to overcome several existing technology-based safety and efficacy issues.
October 5, 2017: Cell Stem Cell
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