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Combinatorial genomics

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https://www.readbyqxmd.com/read/28811376/in-vivo-loss-of-function-screens-identify-kpnb1-as-a-new-druggable-oncogene-in-epithelial-ovarian-cancer
#1
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 15, 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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
https://www.readbyqxmd.com/read/28794031/combinatorial-effects-of-the-glucocorticoid-receptor-and-kr%C3%A3-ppel-like-transcription-factor-15-on-bovine-herpesvirus-1-transcription-and-productive-infection
#8
Fouad S El-Mayet, Laximan Sawant, Prasanth Thunuguntla, Clinton Jones
Bovine herpesvirus 1 (BoHV-1), an important bovine pathogen, establishes life-long latency in sensory neurons. Latently infected calves consistently reactivate from latency following a single intravenous injection of the synthetic corticosteroid dexamethasone. The immediate early transcription unit 1 (IEtu1) promoter, which drives bICP0 and bICP4 expression, is stimulated by dexamethasone because it contains two glucocorticoid receptor (GR) response elements (GREs). Several Krüppel-like transcription factors (KLF), including KLF15, are induced during reactivation from latency and they stimulate certain viral promoters and productive infection...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28781987/next-generation-sequencing-of-carcinoma-of-unknown-primary-reveals-novel-combinatorial-strategies-in-a-heterogeneous-mutational-landscape
#9
Ishwaria M Subbiah, Apostolia Tsimberidou, Vivek Subbiah, Filip Janku, Sinchita Roy-Chowdhuri, David S Hong
BACKGROUND: Advanced carcinoma of unknown primary (CUP) has limited effective therapeutic options given the phenotypic and genotypic diversity. To identify future novel therapeutic strategies we conducted an exploratory analysis of next-generation sequencing (NGS) of relapsed, refractory CUP. METHODS: We identified patients in our phase I clinic where archival tissue was available for a targeted NGS CLIA-certified assay. RESULTS: Of 17 patients tested, 15 (88%) demonstrated genomic alterations (median 2 aberrations; range 0-8, total 59 alterations)...
May 2017: Oncoscience
https://www.readbyqxmd.com/read/28765600/combinatorial-metabolic-engineering-of-pseudomonas-putida-kt2440-for-efficient-mineralization-of-1-2-3-trichloropropane
#10
Ting Gong, Xiaoqing Xu, You Che, Ruihua Liu, Weixia Gao, Fengjie Zhao, Huilei Yu, Jingnan Liang, Ping Xu, Cunjiang Song, Chao Yang
An industrial waste, 1,2,3-trichloropropane (TCP), is toxic and extremely recalcitrant to biodegradation. To date, no natural TCP degraders able to mineralize TCP aerobically have been isolated. In this work, we engineered a biosafety Pseudomonas putida strain KT2440 for aerobic mineralization of TCP by implantation of a synthetic biodegradation pathway into the chromosome and further improved TCP mineralization using combinatorial engineering strategies. Initially, a synthetic pathway composed of haloalkane dehalogenase, haloalcohol dehalogenase and epoxide hydrolase was functionally assembled for the conversion of TCP into glycerol in P...
August 1, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28764701/a-versatile-one-step-crispr-cas9-based-approach-to-plasmid-curing
#11
Ida Lauritsen, Andreas Porse, Morten O A Sommer, Morten H H Nørholm
BACKGROUND: Plasmids are widely used and essential tools in molecular biology. However, plasmids often impose a metabolic burden and are only temporarily useful for genetic engineering, bio-sensing and characterization purposes. While numerous techniques for genetic manipulation exist, a universal tool enabling rapid removal of plasmids from bacterial cells is lacking. RESULTS: Based on replicon abundance and sequence conservation analysis, we show that the vast majority of bacterial cloning and expression vectors share sequence similarities that allow for broad CRISPR-Cas9 targeting...
August 2, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28760855/dual%C3%A2-targeting%C3%A2-of%C3%A2-insulin%C3%A2-receptor%C3%A2-and%C3%A2-kit%C3%A2-in%C3%A2-imatinib-resistant%C3%A2-gastrointestinal%C3%A2-stromal%C3%A2-tumors
#12
Weicai Chen, Ye Kuang, Hai-Bo Qiu, Zhifa Cao, Yuqing Tu, Qing Sheng, Grant Eilers, Quan He, Hai-Long Li, Meijun Zhu, Yuexiang Wang, Rongqing Zhang, Yeqing Wu, Fanguo Meng, Jonathan A Fletcher, Wen-Bin Ou
Oncogenic KIT or PDGFRA receptor tyrosine kinase (RTK) mutations are compelling therapeutic targets in gastrointestinal stromal tumors (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GIST. Most GIST eventually acquire imatinib resistance due to secondary mutations in the KIT kinase domain, but it is unclear whether these genomic resistance mechanisms require other cellular adaptations to create a clinically meaningful imatinib-resistant state...
July 31, 2017: Cancer Research
https://www.readbyqxmd.com/read/28751450/infiltrating-t-cells-increase-ido1-expression-in-glioblastoma-and-contribute-to-decreased-patient-survival
#13
Lijie Zhai, Erik Ladomersky, Kristen L Lauing, Meijing Wu, Matthew Genet, Galina Gritsina, Balázs Győrffy, Priscilla K Brastianos, David Binder, Jeffrey A Sosman, Francis J Giles, C David James, Craig Horbinski, Roger Stupp, Derek A Wainwright
Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.<br /><br />Experimental Design: Patient-resected GBM, the cancer genome atlas, human T cell:GBM co-cultures, as well as nu/nu, NOD-scid and humanized (NSG-SGM3-BLT) mice engrafted human GBM, form the basis of our investigation...
July 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28733422/differences-in-dna-binding-specificity-of-floral-homeotic-protein-complexes-predict-organ-specific-target-genes
#14
Cezary Smaczniak, Jose M Muiño, Dijun Chen, Gerco C Angenent, Kerstin Kaufmann
Floral organ identities in plants are specified by the combinatorial action of homeotic master regulatory transcription factors. How these factors achieve their regulatory specificities is however still largely unclear. Genome-wide in vivo DNA binding data show that homeotic MADS-domain proteins recognize partly distinct genomic regions, suggesting that DNA binding specificity contributes to functional differences of homeotic protein complexes. We used in vitro systematic evolution of ligands by exponential enrichment followed by high throughput DNA sequencing (SELEX-seq) on several floral MADS-domain protein homo- and heterodimers to measure their DNA-binding specificities...
July 21, 2017: Plant Cell
https://www.readbyqxmd.com/read/28732207/a-crispr-resource-for-individual-combinatorial-or-multiplexed-gene-knockout
#15
Nicolas Erard, Simon R V Knott, Gregory J Hannon
We have combined a machine-learning approach with other strategies to optimize knockout efficiency with the CRISPR/Cas9 system. In addition, we have developed a multiplexed sgRNA expression strategy that promotes the functional ablation of single genes and allows for combinatorial targeting. These strategies have been combined to design and construct a genome-wide, sequence-verified, arrayed CRISPR library. This resource allows single-target or combinatorial genetic screens to be carried out at scale in a multiplexed or arrayed format...
July 20, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28718419/targeting-pi3k-signaling-in-combination-cancer-therapy
#16
REVIEW
Elvire Pons-Tostivint, Benoît Thibault, Julie Guillermet-Guibert
Targeting upstream phosphatidylinositol-3-kinases (PI3Ks) in the PI3K/Akt/mTOR pathway appears to be a promising therapy in solid cancers; however, first early clinical trials with PI3K inhibitors in monotherapy have been disappointing. A massive array of preclinical and clinical trials are currently evaluating combinations of PI3K inhibitors in targeted therapies. These combinations include co-treatments with drugs directed against other intra-/extracellular signaling molecules, nuclear hormone receptors, DNA damage repair enzymes, and immune modulators...
June 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28716409/from-experiment-driven-database-analyses-to-database-driven-experiments-in-arabidopsis-thaliana-transcription-factor-research
#17
REVIEW
Reinhard Hehl
Experiment-driven database analysis is employed in forward genetics to predict the function of genes assocíated with a mutant phenotype. These analyses subsequently lead to database-driven experiments involving reverse genetics to verify functional predictions based on bioinformatic analyses. Genomic transcription factors (TFs) are key regulators of gene expression by binding to short regulatory sequences and by interacting with other TFs. Currently more than 2400 TFs are predicted for A. thaliana. As DNA-binding proteins they are particularly amenable to database-driven experiments, especially when their binding site specificities are known...
September 2017: Plant Science: An International Journal of Experimental Plant Biology
https://www.readbyqxmd.com/read/28716006/ethylene-induces-combinatorial-effects-of-histone-h3-acetylation-in-gene-expression-in-arabidopsis
#18
Likai Wang, Fan Zhang, Siddharth Rode, Kevin K Chin, Eun Esther Ko, Jonghwan Kim, Vishwanath R Iyer, Hong Qiao
BACKGROUND: Histone acetylation and deacetylation are essential for gene regulation and have been implicated in the regulation of plant hormone responses. Many studies have indicated the role of histone acetylation in ethylene signaling; however, few studies have investigated how ethylene signaling regulates the genomic landscape of chromatin states. Recently, we found that ethylene can specifically elevate histone H3K14 acetylation and the non-canonical histone H3K23 acetylation in etiolated seedlings and the gene activation is positively associated with the elevation of H3K14Ac and H3K23Ac in response to ethylene...
July 17, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28714992/musashi-1-regulates-the-timing-and-extent-of-meiotic-mrna-translational-activation-by-promoting-the-use-of-specific-cpes
#19
Laure Weill, Eulàlia Belloc, Chiara Lara Castellazzi, Raúl Méndez
The translational reactivation of maternal mRNAs encoding meiotic drivers in vertebrates is accomplished mainly by cytoplasmic polyadenylation. The cytoplasmic polyadenylation elements (CPEs) present in the 3' untranslated regions (3' UTRs) of these transcripts, together with their cognate CPE-binding proteins (CPEBs), define a combinatorial code that determines the timing and extent of translational activation upon meiosis resumption. In addition, the RNA-binding protein Musashi1 (Msi1) regulates polyadenylation of CPE-containing mRNAs by a yet undefined CPEB-dependent or CPEB-independent mechanism...
August 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/28711868/human-ttbk1-ttbk2-and-mark1-kinase-toxicity-in-drosophila-melanogaster-is-exacerbated-by-co-expression-of-human-tau
#20
Josefin Fernius, Annika Starkenberg, Malgorzata Pokrzywa, Stefan Thor
Tau protein is involved in numerous human neurodegenerative diseases, and Tau hyper-phosphorylation has been linked to Tau aggregation and toxicity. Previous studies have addressed toxicity and phospho-biology of human Tau (hTau) in Drosophila melanogaster However, hTau transgenes have most often been randomly inserted in the genome, thus making it difficult to compare between different hTau isoforms and phospho-mutants. In addition, many studies have expressed hTau also in mitotic cells, causing non-physiological toxic effects...
July 15, 2017: Biology Open
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