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Combinatorial genomics

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https://www.readbyqxmd.com/read/28928148/genome-wide-engineering-of-an-infectious-clone-of-herpes-simplex-virus-type-1-using-synthetic-genomics-assembly-methods
#1
Lauren M Oldfield, Peter Grzesik, Alexander A Voorhies, Nina Alperovich, Derek MacMath, Claudia D Najera, Diya Sabrina Chandra, Sanjana Prasad, Vladimir N Noskov, Michael G Montague, Robert M Friedman, Prashant J Desai, Sanjay Vashee
Here, we present a transformational approach to genome engineering of herpes simplex virus type 1 (HSV-1), which has a large DNA genome, using synthetic genomics tools. We believe this method will enable more rapid and complex modifications of HSV-1 and other large DNA viruses than previous technologies, facilitating many useful applications. Yeast transformation-associated recombination was used to clone 11 fragments comprising the HSV-1 strain KOS 152 kb genome. Using overlapping sequences between the adjacent pieces, we assembled the fragments into a complete virus genome in yeast, transferred it into an Escherichia coli host, and reconstituted infectious virus following transfection into mammalian cells...
September 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28926673/combinatorial-genome-and-protein-engineering-yields-monoclonal-antibodies-with-hypergalactosylation-from-cho-cells
#2
Cheng-Yu Chung, Qiong Wang, Shuang Yang, Sean A Ponce, Brian J Kirsch, Hui Zhang, Michael J Betenbaugh
One of the key quality attributes of monoclonal antibodies is the glycan pattern and distribution. Two terminal galactose residues typically represent a small fraction of the total glycans from antibodies. However, antibodies with defined glycosylation properties including enhanced galactosylation have been shown to exhibit altered properties for these important biomedical modalities. In this study, the disruption of two α-2,3 sialyltransferases (ST3GAL4 and ST3GAL6) from Chinese Hamster Ovary (CHO) cells was combined with protein engineering of the Fc region to generate an IgG containing 80% bigalactosylated and fucosylated (G2F) glycoforms...
July 7, 2017: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/28922109/protein-mediated-rna-folding-governs-sequence-specific-interactions-between-rotavirus-genome-segments
#3
Alexander Borodavka, Eric C Dykeman, Waldemar Schrimpf, Don C Lamb
Segmented RNA viruses are ubiquitous pathogens, which include influenza viruses and rotaviruses. A major challenge in understanding their assembly is the combinatorial problem of a non-random selection of a full genomic set of distinct RNAs. This process involves complex RNA-RNA and protein-RNA interactions, which are often obscured by non-specific binding at concentrations approaching in vivo assembly conditions. Here, we present direct experimental evidence of sequence-specific inter-segment interactions between rotavirus RNAs, taking place in a complex RNA- and protein-rich milieu...
September 18, 2017: ELife
https://www.readbyqxmd.com/read/28917257/exploiting-molecular-genomics-in-precision-radiation-oncology-a-marriage-of-biological-and-physical-precision
#4
Janice S H Tan, Xiaotian Lin, Kevin L M Chua, Paula Y Lam, Khee-Chee Soo, Melvin L K Chua
Achieving local tumour control is paramount for cure in head and neck and prostate cancers. With the transition to precision radiotherapy (RT) techniques, survival rates have improved in the majority of these cancers, but a substantial proportion of 30-40% still relapse following primary treatment. Recent large-scale molecular profiling studies have revealed unique biological events that could explain for tumour aggression and resistance to therapies, redefining the molecular taxonomy of head and neck and prostate cancers...
September 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/28906493/rapid-curation-of-gene-disruption-collections-using-knockout-sudoku
#5
Isao A Anzai, Lev Shaket, Oluwakemi Adesina, Michael Baym, Buz Barstow
Knockout Sudoku is a method for the construction of whole-genome knockout collections for a wide range of microorganisms with as little as 3 weeks of dedicated labor and at a cost of ∼$10,000 for a collection for a single organism. The method uses manual 4D combinatorial pooling, next-generation sequencing, and a Bayesian inference algorithm to rapidly process and then accurately annotate the extremely large progenitor transposon insertion mutant collections needed to achieve saturating coverage of complex microbial genomes...
October 2017: Nature Protocols
https://www.readbyqxmd.com/read/28902898/identification-and-characterization-of-preferred-dna-binding-sites-for-the-thermus-thermophilus-transcriptional-regulator-fadr
#6
Minwoo Lee, Hyejin Um, Michael W Van Dyke
One of the primary transcriptional regulators of fatty acid homeostasis in many prokaryotes is the protein FadR. To better understand its biological function in the extreme thermophile Thermus thermophilus HB8, we sought to first determine its preferred DNA-binding sequences in vitro using the combinatorial selection method Restriction Endonuclease Protection, Selection, and Amplification (REPSA) and then use this information to bioinformatically identify potential regulated genes. REPSA determined a consensus FadR-binding sequence 5´-TTRNACYNRGTNYAA-3´, which was further characterized using quantitative electrophoretic mobility shift assays...
2017: PloS One
https://www.readbyqxmd.com/read/28898266/translating-natural-genetic-variation-to-gene-expression-in-a-computational-model-of-the-drosophila-gap-gene-regulatory-network
#7
Vitaly V Gursky, Konstantin N Kozlov, Ivan V Kulakovskiy, Asif Zubair, Paul Marjoram, David S Lawrie, Sergey V Nuzhdin, Maria G Samsonova
Annotating the genotype-phenotype relationship, and developing a proper quantitative description of the relationship, requires understanding the impact of natural genomic variation on gene expression. We apply a sequence-level model of gap gene expression in the early development of Drosophila to analyze single nucleotide polymorphisms (SNPs) in a panel of natural sequenced D. melanogaster lines. Using a thermodynamic modeling framework, we provide both analytical and computational descriptions of how single-nucleotide variants affect gene expression...
2017: PloS One
https://www.readbyqxmd.com/read/28893790/combinatorial-crispr-cas9-and-rnai-attack-on-hiv-1-dna-and-rna-can-lead-to-cross-resistance
#8
Na Zhao, Gang Wang, Atze T Das, Ben Berkhout
Many potent antiviral drugs have been developed against HIV-1 and their combined action is usually successful in achieving durable virus suppression in infected individuals. This success is based on two effects: additive or even synergistic virus inhibition and an increase in the genetic threshold for development of drug-resistance. More recently, several genetic approaches have been developed to attack the HIV-1 genome in a gene therapy setting. We set out to test the combinatorial possibilities for a therapy based on the CRISPR-Cas9 and RNA interference (RNAi) mechanisms that attack the viral DNA and RNA, respectively...
September 11, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28892230/effector-triggered-self-replication-in-coupled-subsystems
#9
Dávid Komáromy, Meniz Tezcan, Gaël Schaeffer, Ivana Marić, Sijbren Otto
In living systems processes like genome duplication and cell division are carefully synchronized through sub-system coupling. If we are to create life de-novo, similar control over essential processes such as self-replication need to be developed. Here we report that coupling two dynamic combinatorial subsystems, featuring two separate building blocks, enables effector-mediated control over the onset of self-replication. The subsystem based on the first building block shows only self-replication, whereas that based on the second one is solely responsive toward a specific external effector molecule...
September 11, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28891214/non-redundant-functions-of-the-dimeric-aba-receptor-bdpyl1-in-the-grass-brachypodium
#10
Oded Pri-Tal, Lidor Shaar-Moshe, Gil Wiseglass, Zvi Peleg, Assaf Mosquna
Abiotic stresses have severe detrimental effects on agricultural productivity worldwide. ABA levels rise in response to abiotic stresses, and play a role in coordinating physiological responses. ABA elicits its effects by binding a family of soluble receptors, increasing affinity of the receptors to type 2C phosphatases (PP2Cs) leading to phosphatase inhibition. In the current study, we conducted a comprehensive analysis of the ABA signaling pathway in the cereal model grass Brachypodium distachyon. The Brachypodium genome encodes a family of ten functionally conserved ABA receptors...
September 11, 2017: Plant Journal: for Cell and Molecular Biology
https://www.readbyqxmd.com/read/28874521/combinatorial-interaction-network-of-abscisic-acid-receptors-and-coreceptors-from-arabidopsis-thaliana
#11
Stefanie V Tischer, Christian Wunschel, Michael Papacek, Karin Kleigrewe, Thomas Hofmann, Alexander Christmann, Erwin Grill
The phytohormone abscisic acid (ABA) is induced in response to abiotic stress to mediate plant acclimation to environmental challenge. Key players of the ABA-signaling pathway are the ABA-binding receptors (RCAR/PYR1/PYL), which, together with a plant-specific subclade of protein phosphatase 2C (PP2C), form functional holoreceptors. The Arabidopsis genome encodes nine PP2C coreceptors and 14 different RCARs, which can be divided into three subfamilies. The presence of these gene families in higher plants points to the existence of an intriguing regulatory network and poses questions as to the functional compatibility and specificity of receptor-coreceptor interactions...
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28844952/targeting-cholangiocarcinoma
#12
REVIEW
Joachim C Mertens, Sumera Rizvi, Gregory J Gores
Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA...
August 24, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28842878/nucleoid-associated-proteins-genome-level-occupancy-and-expression-analysis
#13
Parul Singh, Aswin Sai Narain Seshasayee
The advent of Chromatin Immunoprecipitation sequencing (ChIP-Seq) has allowed the identification of genomic regions bound by a DNA binding protein in-vivo on a genome-wide scale. The impact of the DNA binding protein on gene expression can be addressed using transcriptome experiments in appropriate genetic settings. Overlaying the above two sources of data enables us to dissect the direct and indirect effects of a DNA binding protein on gene expression. Application of these techniques to Nucleoid Associated Proteins (NAPs) and Global Transcription Factors (GTFs) has underscored the complex relationship between DNA-protein interactions and gene expression change, highlighting the role of combinatorial control...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28811376/in-vivo-loss-of-function-screens-identify-kpnb1-as-a-new-druggable-oncogene-in-epithelial-ovarian-cancer
#14
Michiko Kodama, Takahiro Kodama, Justin Y Newberg, Hiroyuki Katayama, Makoto Kobayashi, Samir M Hanash, Kosuke Yoshihara, Zhubo Wei, Jean C Tien, Roberto Rangel, Kae Hashimoto, Seiji Mabuchi, Kenjiro Sawada, Tadashi Kimura, Neal G Copeland, Nancy A Jenkins
Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further...
August 29, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28806393/craf-gene-fusions-in-pediatric-low-grade-gliomas-define-a-distinct-drug-response-based-on-dimerization-profiles
#15
P Jain, T M Fierst, H J Han, T E Smith, A Vakil, P J Storm, A C Resnick, A J Waanders
Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways...
August 14, 2017: Oncogene
https://www.readbyqxmd.com/read/28803482/corynebacterium-glutamicum-chassis-c1-building-and-testing-a-novel-platform-host-for-synthetic-biology-and-industrial-biotechnology
#16
Meike Baumgart, Simon Unthan, Ramona Kloss, Andreas Radek, Tino Polen, Niklas Tenhaef, Moritz Fabian Müller, Andreas Küberl, Daniel Siebert, Natalie Brühl, Kay Marin, Stephan Hans, Reinhard Krämer, Michael Bott, Joern Kalinowski, Wolfgang Wiechert, Gerd Seibold, Julia Frunzke, Christian Rückert, Volker Wendisch, Stephan Noack
Targeted top-down strategies for genome reduction are considered to have a high potential for providing robust basic strains for synthetic biology and industrial biotechnology. Recently, we created a library of 26 genome-reduced strains of Corynebacterium glutamicum carrying broad deletions in single gene clusters and showing wild-type-like biological fitness. Here, we proceeded with combinatorial deletions of these irrelevant gene clusters in two parallel orders and the resulting library of 28 strains was characterized under various environmental conditions...
August 14, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28802167/induction-of-senescence-in-cancer-cells-by-5-aza-2-deoxycytidine-bioinformatics-and-experimental-insights-to-its-targets
#17
Jayarani F Putri, Nashi Widodo, Kazuichi Sakamoto, Sunil C Kaul, Renu Wadhwa
5'-Aza-2'-deoxycytidine (5-Aza-dC) is a demethylating drug that causes genome-wide hypomethylation resulting in the expression of several tumor suppressor genes causing growth arrest of cancer cells. Cancer is well established as a multifactorial disease and requires multi-module therapeutics. Search for new drugs and their approval by FDA takes a long time. Keeping this in view, research on new functions of FDA-approved anticancer drugs is desired to expand the list of multi-module functioning drugs for cancer therapy...
August 2, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28802047/dual-ifgmosaic-a-versatile-method-for-multispectral-and-combinatorial-mosaic-gene-function-analysis
#18
Samuel Pontes-Quero, Luis Heredia, Verónica Casquero-García, Macarena Fernández-Chacón, Wen Luo, Ana Hermoso, Mayank Bansal, Irene Garcia-Gonzalez, Maria S Sanchez-Muñoz, Juan R Perea, Adrian Galiana-Simal, Iker Rodriguez-Arabaolaza, Sergio Del Olmo-Cabrera, Susana F Rocha, Luis M Criado-Rodriguez, Giovanna Giovinazzo, Rui Benedito
Improved methods for manipulating and analyzing gene function have provided a better understanding of how genes work during organ development and disease. Inducible functional genetic mosaics can be extraordinarily useful in the study of biological systems; however, this experimental approach is still rarely used in vertebrates. This is mainly due to technical difficulties in the assembly of large DNA constructs carrying multiple genes and regulatory elements and their targeting to the genome. In addition, mosaic phenotypic analysis, unlike classical single gene-function analysis, requires clear labeling and detection of multiple cell clones in the same tissue...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28800965/the-crispr-cas9-facilitated-multiplex-pathway-optimization-cfpo-technique-and-its-application-to-improve-the-escherichia-coli-xylose-utilization-pathway
#19
Xinna Zhu, Dongdong Zhao, Huanna Qiu, Feiyu Fan, Shuli Man, Changhao Bi, Xueli Zhang
One of the most important research subjects of metabolic engineering is the pursuit of balanced metabolic pathways, which requires the modulation of expression of many genes. However, simultaneously modulating multiple genes on the chromosome remains challenging in prokaryotic organisms, including the industrial workhorse - Escherichia coli. In this work, the CRISPR/Cas9-facilitated multiplex pathway optimization (CFPO) technique was developed to simultaneously modulate the expression of multiple genes on the chromosome...
August 9, 2017: Metabolic Engineering
https://www.readbyqxmd.com/read/28797519/treatment-of-acute-myeloid-leukemia-in-the-next-decade-towards-real-time-functional-testing-and-personalized-medicine
#20
REVIEW
Stephen Sze-Yuen Lam, Alex Bai-Liang He, Anskar Yu-Hung Leung
Information arising from next generation sequencing of leukemia genome has shed important light on the heterogeneous and combinatorial driver events in acute myeloid leukemia (AML). It has also provided insight into its intricate signaling pathways operative in the disease pathogenesis. These have also become biomarkers and targets for therapeutic intervention. Emerging evidence from in vitro drug screening has demonstrated its potential value in predicting clinical drug responses in specific AML subtypes. However, the best culture conditions and readouts have yet to be standardized and the drugs included in these screening exercises frequently revised in view of the rapid emergence of new therapeutic agents in the oncology field...
August 4, 2017: Blood Reviews
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