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https://www.readbyqxmd.com/read/29224783/in%C3%A2-vivo-target-gene-activation-via-crispr-cas9-mediated-trans-epigenetic-modulation
#1
Hsin-Kai Liao, Fumiyuki Hatanaka, Toshikazu Araoka, Pradeep Reddy, Min-Zu Wu, Yinghui Sui, Takayoshi Yamauchi, Masahiro Sakurai, David D O'Keefe, Estrella Núñez-Delicado, Pedro Guillen, Josep M Campistol, Cheng-Jang Wu, Li-Fan Lu, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte
Current genome-editing systems generally rely on inducing DNA double-strand breaks (DSBs). This may limit their utility in clinical therapies, as unwanted mutations caused by DSBs can have deleterious effects. CRISPR/Cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating DSBs. However, in vivo implementation of this gain-of-function system has proven difficult. Here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling...
November 30, 2017: Cell
https://www.readbyqxmd.com/read/29223136/allele-exchange-at-the-epsps-locus-confers-glyphosate-tolerance-in-cassava
#2
Aaron W Hummel, Raj Deepika Chauhan, Tomas Cermak, Andrew M Mutka, Anupama Vijayaraghavan, Adam Boyher, Colby G Starker, Rebecca Bart, Daniel F Voytas, Nigel J Taylor
Effective weed control can protect yields of cassava (Manihot esculenta) storage roots (Doll and Piedrahita Cañola, 1978). Farmers could benefit from using herbicide with a tolerant cultivar. We applied traditional transgenesis and gene editing to generate robust glyphosate tolerance in cassava. By comparing promoters regulating expression of transformed 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) genes with various paired amino acid substitutions, we found that strong constitutive expression is required to achieve glyphosate tolerance during in vitro selection and in whole cassava plants...
December 9, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/29222528/structure-and-dynamics-of-cas9-hnh-domain-catalytic-state
#3
Zhicheng Zuo, Jin Liu
The bacterial CRISPR-Cas9 immune system has been harnessed as a powerful and versatile genome-editing tool and holds immense promise for future therapeutic applications. Despite recent advances in understanding Cas9 structures and its functional mechanism, little is known about the catalytic state of the Cas9 HNH nuclease domain, and identifying how the divalent metal ions affect the HNH domain conformational transition remains elusive. A deeper understanding of Cas9 activation and its cleavage mechanism can enable further optimization of Cas9-based genome-editing specificity and efficiency...
December 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29222508/crispr-cpf1-mediates-efficient-homology-directed-repair-and-temperature-controlled-genome-editing
#4
Miguel A Moreno-Mateos, Juan P Fernandez, Romain Rouet, Charles E Vejnar, Maura A Lane, Emily Mis, Mustafa K Khokha, Jennifer A Doudna, Antonio J Giraldez
Cpf1 is a novel class of CRISPR-Cas DNA endonucleases, with a wide range of activity across different eukaryotic systems. Yet, the underlying determinants of this variability are poorly understood. Here, we demonstrate that LbCpf1, but not AsCpf1, ribonucleoprotein complexes allow efficient mutagenesis in zebrafish and Xenopus. We show that temperature modulates Cpf1 activity by controlling its ability to access genomic DNA. This effect is stronger on AsCpf1, explaining its lower efficiency in ectothermic organisms...
December 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/29222162/dual-inhibition-of-pik3c3-and-fgfr-as-a-new-therapeutic-approach-to-treat-bladder-cancer
#5
Chun-Han Chen, C Changou, Tsung-Han Hsieh, Yu-Ching Lee, Cheng-Ying Chu, Kai-Cheng Hsu, Hao-Ching Wang, Yu-Chen Lin, Yan-Ni Lo, Yun-Ru Liu, Jing-Ping Liou, Yun Yen
PURPOSE: MPT0L145 has been developed as a FGFR inhibitor exhibiting significant anti-bladder cancer activity in vitro and in vivo via promoting autophagy-dependent cell death. Here, we aim to elucidate the underlying mechanisms. EXPERIMENTAL DESIGN: Autophagy flux, morphology and intracellular organelles were evaluated by western blotting, transmission electron microscope and fluorescence microscope. Molecular docking, surface plasmon resonance assay were performed to identify drug-protein interaction...
December 8, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29221806/characterization-of-gene-alterations-following-editing-of-the-%C3%AE-globin-gene-locus-in-hematopoietic-stem-progenitor-cells
#6
Joseph Long, Megan D Hoban, Aaron R Cooper, Michael L Kaufman, Caroline Y Kuo, Beatriz Campo-Fernandez, Dianne Lumaquin, Roger P Hollis, Xiaoyan Wang, Donald B Kohn, Zulema Romero
The use of engineered nucleases combined with a homologous DNA donor template can result in targeted gene correction of the sickle cell disease mutation in hematopoietic stem and progenitor cells. However, because of the high homology between the adjacent human β- and δ-globin genes, off-target cleavage is observed at δ-globin when using some endonucleases targeted to the sickle mutation in β-globin. Introduction of multiple double-stranded breaks by endonucleases has the potential to induce intergenic alterations...
November 9, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29219081/whole-genome-analysis-of-crispr-cas9-sgrna-off-target-homologies-via-an-efficient-computational-algorithm
#7
Hong Zhou, Michael Zhou, Daisy Li, Joseph Manthey, Ekaterina Lioutikova, Hong Wang, Xiao Zeng
BACKGROUND: The beauty and power of the genome editing mechanism, CRISPR Cas9 endonuclease system, lies in the fact that it is RNA-programmable such that Cas9 can be guided to any genomic loci complementary to a 20-nt RNA, single guide RNA (sgRNA), to cleave double stranded DNA, allowing the introduction of wanted mutations. Unfortunately, it has been reported repeatedly that the sgRNA can also guide Cas9 to off-target sites where the DNA sequence is homologous to sgRNA. RESULTS: Using human genome and Streptococcus pyogenes Cas9 (SpCas9) as an example, this article mathematically analyzed the probabilities of off-target homologies of sgRNAs and discovered that for large genome size such as human genome, potential off-target homologies are inevitable for sgRNA selection...
November 17, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29215091/cancer-induction-and-suppression-with-transcriptional-control-and-epigenome-editing-technologies
#8
REVIEW
Shota Nakade, Takashi Yamamoto, Tetsushi Sakuma
Cancer epigenetics is one of the most important research subjects in dissecting cancer mechanisms and therapeutic targets because the emergence and malignant transformation of various cancers are caused by unnatural expression of cancer-related genes attributed to their epigenetic errors. The original concept of cancer epigenetics basically stands on the analysis of the epigenetic status in naturally occurring cancer cells; however, the rapidly emerging technology called epigenome editing would change this situation drastically...
November 14, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/29215041/crispr-cas9-delivery-with-one-single-adenoviral-vector-devoid-of-all-viral-genes
#9
Eric Ehrke-Schulz, Maren Schiwon, Theo Leitner, Stephan Dávid, Thorsten Bergmann, Jing Liu, Anja Ehrhardt
The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 system revolutionized the field of gene editing but viral delivery of the CRISPR/Cas9 system has not been fully explored. Here we adapted clinically relevant high-capacity adenoviral vectors (HCAdV) devoid of all viral genes for the delivery of the CRISPR/Cas9 machinery using a single viral vector. We present a platform enabling fast transfer of the Cas9 gene and gRNA expression units into the HCAdV genome including the option to choose between constitutive or inducible Cas9 expression and gRNA multiplexing...
December 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29211501/viral-subversion-of-apobec3s-lessons-for-anti-tumor-immunity-and-tumor-immunotherapy
#10
Faezeh Borzooee, Mahdi Asgharpour, Emma Quinlan, Michael D Grant, Mani Larijani
APOBEC3s (A3) are endogenous DNA-editing enzymes that are expressed in immune cells including T lymphocytes. A3s target and mutate the genomes of retroviruses that infect immune tissues such as the human immunodeficiency virus (HIV). Therefore, A3s were classically defined as host anti-viral innate immune factors. In contrast, we and others showed that A3s can also benefit the virus by mediating escape from adaptive immune recognition and drugs. Crucially, whether A3-mediated mutations help or hinder HIV, is not up to chance...
December 6, 2017: International Reviews of Immunology
https://www.readbyqxmd.com/read/29210569/modulating-dna-repair-pathways-to-improve-precision-genome-engineering
#11
Katherine S Pawelczak, Navnath S Gavande, Pamela S VanderVere-Carozza, John J Turchi
Programmable nucleases like the popular CRISPR/Cas9 system allow for precision genome engineering by inducing a site-specific DNA double strand break (DSB) within a genome. The DSB is repaired by endogenous DNA repair pathways, either non-homologous end joining (NHEJ) or homology directed repair (HDR). The predominant and error-prone NHEJ pathway often results in small nucleotide insertions or deletions that can be used to construct knockout alleles. Alternatively, HDR activity can result in precise modification incorporating exogenous DNA fragments into the cut site...
December 6, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/29210156/selective-nascent-polymer-catch-and-release-enables-scalable-isolation-of-multi-kilobase-single-stranded-dna
#12
Elisha Krieg, William M Shih
Scalable methods currently are lacking for isolation of long ssDNA, an important material for numerous biotechnological applications. Conventional biomolecule purification strategies achieve target capture using solid supports, which are limited in scale and susceptible to contamination due to nonspecific adsorption and desorption on the substrate surface. We herein disclose Selective Nascent Polymer Catch and Release (SNAPCAR), a method that utilizes the reactivity of growing poly(acrylamide-co-acrylate) chains to capture acrylamide-labeled molecules in free solution...
December 5, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/29208987/genome-wide-dna-methylation-changes-associated-with-olfactory-learning-and-memory-in-apis-mellifera
#13
You Li, Li-Zhen Zhang, Yao Yi, Wan-Wan Hu, Ya-Hui Guo, Zhi-Jiang Zeng, Zachary-Y Huang, Zi-Long Wang
The honeybee is a model organism for studying learning and memory formation and its underlying molecular mechanisms. While DNA methylation is well studied in caste differentiation, its role in learning and memory is not clear in honeybees. Here, we analyzed genome-wide DNA methylation changes during olfactory learning and memory process in A. mellifera using whole genome bisulfite sequencing (WGBS) method. A total of 853 significantly differentially methylated regions (DMRs) and 963 differentially methylated genes (DMGs) were identified...
December 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29208717/efficient-targeted-dna-editing-and-replacement-in-chlamydomonas-reinhardtii-using-cpf1-ribonucleoproteins-and-single-stranded-dna
#14
Aron Ferenczi, Douglas Euan Pyott, Andromachi Xipnitou, Attila Molnar
The green alga Chlamydomonas reinhardtii is an invaluable reference organism to research fields including algal, plant, and ciliary biology. Accordingly, decades-long standing inefficiencies in targeted nuclear gene editing broadly hinder Chlamydomonas research. Here we report that single-step codelivery of CRISPR/Cpf1 ribonucleoproteins with single-stranded DNA repair templates results in precise and targeted DNA replacement with as much as ∼10% efficiency in C. reinhardtii We demonstrate its use in transgene- and selection-free generation of sequence-specific mutations and epitope tagging at an endogenous locus...
December 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29206307/osteoprotection-through-the-deletion-of-the-transcription-factor-ror%C3%AE-in-mice
#15
Joshua N Farr, Megan M Weivoda, Kristy M Nicks, Daniel G Fraser, Brittany A Negley, Jennifer L Onken, Brianne S Thicke, Ming Ruan, Hong Liu, Douglas Forrest, John R Hawse, Sundeep Khosla, David G Monroe
There is a clinical need to identify new molecular targets for the treatment of osteoporosis, particularly those that simultaneously inhibit bone resorption while stimulating bone formation. We have previously shown in overexpression studies that retinoic acid receptor-related orphan receptor β (Rorβ) suppresses in vitro osteoblast differentiation. In addition, the expression of Rorβ is markedly increased in bone marrow-derived mesenchymal stromal cells with aging in both mice and humans. Here we establish a critical role for Rorβ in regulating bone metabolism using a combination of in vitro and in vivo studies...
December 5, 2017: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29205437/mrna-traffic-control-reviewed-n6-methyladenosine-m6-a-takes-the-driver-s-seat
#16
REVIEW
Abhirami Visvanathan, Kumaravel Somasundaram
Messenger RNA is a flexible tool box that plays a key role in the dynamic regulation of gene expression. RNA modifications variegate the message conveyed by the mRNA. Similar to DNA and histone modifications, mRNA modifications are reversible and play a key role in the regulation of molecular events. Our understanding about the landscape of RNA modifications is still rudimentary in contrast to DNA and histone modifications. The major obstacle has been the lack of sensitive detection methods since they are non-editing events...
December 4, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/29202040/a-simple-and-universal-system-for-gene-manipulation-in-aspergillus-fumigatus-in-vitro-assembled-cas9-guide-rna-ribonucleoproteins-coupled-with-microhomology-repair-templates
#17
Qusai Al Abdallah, Wenbo Ge, Jarrod R Fortwendel
CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 is a novel genome-editing system that has been successfully established in Aspergillus fumigatus. However, the current state of the technology relies heavily on DNA-based expression cassettes for delivering Cas9 and the guide RNA (gRNA) to the cell. Therefore, the power of the technology is limited to strains that are engineered to express Cas9 and gRNA. To overcome such limitations, we developed a simple and universal CRISPR-Cas9 system for gene deletion that works across different genetic backgrounds of A...
November 2017: MSphere
https://www.readbyqxmd.com/read/29197418/tagging-to-endogenous-genes-of-plasmodium-falciparum-using-crispr-cas9
#18
Dexuan Kuang, Jichen Qiao, Zhou Li, Weiwei Wang, Hui Xia, Lubin Jiang, Jiejie Dai, Qiang Fang, Xueyu Dai
BACKGROUND: Plasmodium falciparum is the deadliest malaria parasite. Currently, there are seldom commercial antibodies against P. falciparum proteins, which greatly limits the study on Plasmodium. CRISPR/Cas9 is an efficient genome editing method, which has been employed in various organisms. However, the use of this technique in P. falciparum is still limited to gene knockout, site-specific mutation and generation of green fluorescent protein (GFP) reporter line with disruption of inserted sites...
December 2, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/29195281/thermodynamic-framework-for-information-in-nanoscale-systems-with-memory
#19
J Ricardo Arias-Gonzalez
Information is represented by linear strings of symbols with memory that carry errors as a result of their stochastic nature. Proofreading and edition are assumed to improve certainty although such processes may not be effective. Here, we develop a thermodynamic theory for material chains made up of nanoscopic subunits with symbolic meaning in the presence of memory. This framework is based on the characterization of single sequences of symbols constructed under a protocol and is used to derive the behavior of ensembles of sequences similarly constructed...
November 28, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29192328/crispr-cas9-mediated-knockout-of-pissk1-reveals-essential-role-of-s-locus-f-box-protein-containing-scf-complexes-in-recognition-of-non-self-s-rnases-during-cross-compatible-pollination-in-self-incompatible-petunia-inflata
#20
Linhan Sun, Teh-Hui Kao
Function of Petunia PiSSK1. Self-incompatibility (SI), an inbreeding-preventing mechanism, is regulated in Petunia inflata by the polymorphic S-locus, which houses multiple pollen-specific S-locus F-box (SLF) genes and a single pistil-specific S-RNase gene. S 2-haplotype and S 3-haplotype possess the same 17 polymorphic SLF genes (named SLF1 to SLF17), and each SLF protein produced in pollen is assembled into an SCF (Skp1-Cullin1-F-box) E3 ubiquitin ligase complex. A complete suite of SLF proteins is thought to collectively interact with all non-self S-RNases to mediate their ubiquitination and degradation by the 26S proteasome, allowing cross-compatible pollination...
November 30, 2017: Plant Reproduction
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