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Mouse Get4 Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Get4 Knockout Project (CRISPR/Cas9) Objective: To create a Get4 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Get4 gene (NCBI Reference Sequence: NM_026269 ; Ensembl: ENSMUSG00000025858 ) is located on Mouse chromosome 5. 9 exons are identified, with the ATG start codon in exon 1 and the TGA stop codon in exon 9 (Transcript: ENSMUST00000026976). Exon 2~8 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Exon 2 starts from about 15.9% of the coding region. Exon 2~8 covers 75.43% of the coding region. The size of effective KO region: ~4995 bp. The KO region does not have any other known gene. Page 1 of 9 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 2 3 4 5 6 7 8 9 Legends Exon of mouse Get4 Knockout region Page 2 of 9 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 2 is aligned with itself to determine if there are tandem repeats. No significant tandem repeat is found in the dot plot matrix. So this region is suitable for PCR screening or sequencing analysis. Overview of the Dot Plot (down) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 1505 bp section downstream of Exon 8 is aligned with itself to determine if there are tandem repeats. -
Essential Genes and Their Role in Autism Spectrum Disorder
University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Essential Genes And Their Role In Autism Spectrum Disorder Xiao Ji University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Bioinformatics Commons, and the Genetics Commons Recommended Citation Ji, Xiao, "Essential Genes And Their Role In Autism Spectrum Disorder" (2017). Publicly Accessible Penn Dissertations. 2369. https://repository.upenn.edu/edissertations/2369 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2369 For more information, please contact [email protected]. Essential Genes And Their Role In Autism Spectrum Disorder Abstract Essential genes (EGs) play central roles in fundamental cellular processes and are required for the survival of an organism. EGs are enriched for human disease genes and are under strong purifying selection. This intolerance to deleterious mutations, commonly observed haploinsufficiency and the importance of EGs in pre- and postnatal development suggests a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. More and more genetic evidence points to a polygenic model of ASD and it is estimated that hundreds of genes contribute to ASD. The central question addressed in this dissertation is whether genes with a strong effect on survival and fitness (i.e. EGs) play a specific oler in ASD risk. I compiled a comprehensive catalog of 3,915 mammalian EGs by combining human orthologs of lethal genes in knockout mice and genes responsible for cell-based essentiality. -
Inhibition of SNW1 Association with Spliceosomal Proteins Promotes
Cancer Medicine Open Access ORIGINAL RESEARCH Inhibition of SNW1 association with spliceosomal proteins promotes apoptosis in breast cancer cells Naoki Sato1, Masao Maeda2, Mai Sugiyama2, Satoko Ito2, Toshinori Hyodo2, Akio Masuda3, Nobuyuki Tsunoda1, Toshio Kokuryo1, Michinari Hamaguchi2, Masato Nagino1 & Takeshi Senga2 1Department of Surgical Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan 2Division of Cancer Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan 3Division of Neurogenetics, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan Keywords Abstract Apoptosis, EFTUD2, PRPF8, RNA splicing, SNRNP200, SNW1 RNA splicing is a fundamental process for protein synthesis. Recent studies have reported that drugs that inhibit splicing have cytotoxic effects on various Correspondence tumor cell lines. In this report, we demonstrate that depletion of SNW1, a Takeshi Senga, 65 Tsurumai, Showa, Nagoya component of the spliceosome, induces apoptosis in breast cancer cells. Proteo- 466-8550, Japan. Tel: 81-52-744-2463; mics and biochemical analyses revealed that SNW1 directly associates with Fax: 81-52-744-2464; other spliceosome components, including EFTUD2 (Snu114) and SNRNP200 E-mail: [email protected] (Brr2). The SKIP region of SNW1 interacted with the N-terminus of EFTUD2 Funding Information as well as two independent regions in the C-terminus of SNRNP200. Similar to This research was funded by a grant from SNW1 depletion, knockdown of EFTUD2 increased the numbers of apoptotic the Ministry of Education, Culture, Sports, cells. Furthermore, we demonstrate that exogenous expression of either the Science and Technology of Japan SKIP region of SNW1 or the N-terminus region of EFTUD2 significantly pro- (Nanomedicine molecular science, 23107010. -
Emergence of the Noncoding Cancer Genome: a Target of Genetic and Epigenetic Alterations
Published OnlineFirst October 19, 2016; DOI: 10.1158/2159-8290.CD-16-0745 REVIEW Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations Stanley Zhou 1 , 2 , Aislinn E. Treloar 1 , 2 , and Mathieu Lupien 1 , 2 , 3 ABSTRACT The emergence of whole-genome annotation approaches is paving the way for the comprehensive annotation of the human genome across diverse cell and tissue types exposed to various environmental conditions. This has already unmasked the positions of thou- sands of functional cis-regulatory elements integral to transcriptional regulation, such as enhancers, promoters, and anchors of chromatin interactions that populate the noncoding genome. Recent studies have shown that cis-regulatory elements are commonly the targets of genetic and epigenetic altera- tions associated with aberrant gene expression in cancer. Here, we review these fi ndings to showcase the contribution of the noncoding genome and its alteration in the development and progression of can- cer. We also highlight the opportunities to translate the biological characterization of genetic and epi- genetic alterations in the noncoding cancer genome into novel approaches to treat or monitor disease. Signifi cance: The majority of genetic and epigenetic alterations accumulate in the noncoding genome throughout oncogenesis. Discriminating driver from passenger events is a challenge that holds great promise to improve our understanding of the etiology of different cancer types. Advancing our under- standing of the noncoding cancer genome may thus identify new therapeutic opportunities and acceler- ate our capacity to fi nd improved biomarkers to monitor various stages of cancer development. Cancer Discov; 6(11); 1215–29. -
Nuclear PTEN Safeguards Pre-Mrna Splicing to Link Golgi Apparatus for Its Tumor Suppressive Role
ARTICLE DOI: 10.1038/s41467-018-04760-1 OPEN Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role Shao-Ming Shen1, Yan Ji2, Cheng Zhang1, Shuang-Shu Dong2, Shuo Yang1, Zhong Xiong1, Meng-Kai Ge1, Yun Yu1, Li Xia1, Meng Guo1, Jin-Ke Cheng3, Jun-Ling Liu1,3, Jian-Xiu Yu1,3 & Guo-Qiang Chen1 Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are 1234567890():,; largely unknown. Here we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in a phosphatase-independent manner, and identify 262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. We also identify a new exon 2b in GOLGA2 transcript and the exon exclusion contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors brefeldin A and golgicide A. Our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers. 1 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China. 2 Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai 200025, China. -
Modulation of STAT Signaling by STAT-Interacting Proteins
Oncogene (2000) 19, 2638 ± 2644 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Modulation of STAT signaling by STAT-interacting proteins K Shuai*,1 1Departments of Medicine and Biological Chemistry, University of California, Los Angeles, California, CA 90095, USA STATs (signal transducer and activator of transcription) play important roles in numerous cellular processes Interaction with non-STAT transcription factors including immune responses, cell growth and dierentia- tion, cell survival and apoptosis, and oncogenesis. In Studies on the promoters of a number of IFN-a- contrast to many other cellular signaling cascades, the induced genes identi®ed a conserved DNA sequence STAT pathway is direct: STATs bind to receptors at the named ISRE (interferon-a stimulated response element) cell surface and translocate into the nucleus where they that mediates IFN-a response (Darnell, 1997; Darnell function as transcription factors to trigger gene activa- et al., 1994). Stat1 and Stat2, the ®rst known members tion. However, STATs do not act alone. A number of of the STAT family, were identi®ed in the transcription proteins are found to be associated with STATs. These complex ISGF-3 (interferon-stimulated gene factor 3) STAT-interacting proteins function to modulate STAT that binds to ISRE (Fu et al., 1990, 1992; Schindler et signaling at various steps and mediate the crosstalk of al., 1992). ISGF-3 consists of a Stat1:Stat2 heterodimer STATs with other cellular signaling pathways. This and a non-STAT protein named p48, a member of the article reviews the roles of STAT-interacting proteins in IRF (interferon regulated factor) family (Levy, 1997). -
Ubiquitin-Dependent Regulation of the WNT Cargo Protein EVI/WLS Handelt Es Sich Um Meine Eigenständig Erbrachte Leistung
DISSERTATION submitted to the Combined Faculty of Natural Sciences and Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences presented by Lucie Magdalena Wolf, M.Sc. born in Nuremberg, Germany Date of oral examination: 2nd February 2021 Ubiquitin-dependent regulation of the WNT cargo protein EVI/WLS Referees: Prof. Dr. Michael Boutros apl. Prof. Dr. Viktor Umansky If you don’t think you might, you won’t. Terry Pratchett This work was accomplished from August 2015 to November 2020 under the supervision of Prof. Dr. Michael Boutros in the Division of Signalling and Functional Genomics at the German Cancer Research Center (DKFZ), Heidelberg, Germany. Contents Contents ......................................................................................................................... ix 1 Abstract ....................................................................................................................xiii 1 Zusammenfassung .................................................................................................... xv 2 Introduction ................................................................................................................ 1 2.1 The WNT signalling pathways and cancer ........................................................................ 1 2.1.1 Intercellular communication ........................................................................................ 1 2.1.2 WNT ligands are conserved morphogens ................................................................. -
Open Data for Differential Network Analysis in Glioma
International Journal of Molecular Sciences Article Open Data for Differential Network Analysis in Glioma , Claire Jean-Quartier * y , Fleur Jeanquartier y and Andreas Holzinger Holzinger Group HCI-KDD, Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz 2/V, 8036 Graz, Austria; [email protected] (F.J.); [email protected] (A.H.) * Correspondence: [email protected] These authors contributed equally to this work. y Received: 27 October 2019; Accepted: 3 January 2020; Published: 15 January 2020 Abstract: The complexity of cancer diseases demands bioinformatic techniques and translational research based on big data and personalized medicine. Open data enables researchers to accelerate cancer studies, save resources and foster collaboration. Several tools and programming approaches are available for analyzing data, including annotation, clustering, comparison and extrapolation, merging, enrichment, functional association and statistics. We exploit openly available data via cancer gene expression analysis, we apply refinement as well as enrichment analysis via gene ontology and conclude with graph-based visualization of involved protein interaction networks as a basis for signaling. The different databases allowed for the construction of huge networks or specified ones consisting of high-confidence interactions only. Several genes associated to glioma were isolated via a network analysis from top hub nodes as well as from an outlier analysis. The latter approach highlights a mitogen-activated protein kinase next to a member of histondeacetylases and a protein phosphatase as genes uncommonly associated with glioma. Cluster analysis from top hub nodes lists several identified glioma-associated gene products to function within protein complexes, including epidermal growth factors as well as cell cycle proteins or RAS proto-oncogenes. -
Product Datasheet GET4 Overexpression Lysate
Product Datasheet GET4 Overexpression Lysate NBL1-08544 Unit Size: 0.1 mg Store at -80C. Avoid freeze-thaw cycles. Protocols, Publications, Related Products, Reviews, Research Tools and Images at: www.novusbio.com/NBL1-08544 Updated 3/17/2020 v.20.1 Earn rewards for product reviews and publications. Submit a publication at www.novusbio.com/publications Submit a review at www.novusbio.com/reviews/destination/NBL1-08544 Page 1 of 2 v.20.1 Updated 3/17/2020 NBL1-08544 GET4 Overexpression Lysate Product Information Unit Size 0.1 mg Concentration The exact concentration of the protein of interest cannot be determined for overexpression lysates. Please contact technical support for more information. Storage Store at -80C. Avoid freeze-thaw cycles. Buffer RIPA buffer Target Molecular Weight 36.3 kDa Product Description Description Transient overexpression lysate of chromosome 7 open reading frame 20 (C7orf20) The lysate was created in HEK293T cells, using Plasmid ID RC200220 and based on accession number NM_015949. The protein contains a C- MYC/DDK Tag. Gene ID 51608 Gene Symbol GET4 Species Human Notes HEK293T cells in 10-cm dishes were transiently transfected with a non-lipid polymer transfection reagent specially designed and manufactured for large volume DNA transfection. Transfected cells were cultured for 48hrs before collection. The cells were lysed in modified RIPA buffer (25mM Tris-HCl pH7.6, 150mM NaCl, 1% NP-40, 1mM EDTA, 1xProteinase inhibitor cocktail mix, 1mM PMSF and 1mM Na3VO4, and then centrifuged to clarify the lysate. Protein concentration was measured by BCA protein assay kit.This product is manufactured by and sold under license from OriGene Technologies and its use is limited solely for research purposes. -
Bioinformatics Tools for the Analysis of Gene-Phenotype Relationships Coupled with a Next Generation Chip-Sequencing Data Processing Pipeline
Bioinformatics Tools for the Analysis of Gene-Phenotype Relationships Coupled with a Next Generation ChIP-Sequencing Data Processing Pipeline Erinija Pranckeviciene Thesis submitted to the Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirements for the Doctorate in Philosophy degree in Cellular and Molecular Medicine Department of Cellular and Molecular Medicine Faculty of Medicine University of Ottawa c Erinija Pranckeviciene, Ottawa, Canada, 2015 Abstract The rapidly advancing high-throughput and next generation sequencing technologies facilitate deeper insights into the molecular mechanisms underlying the expression of phenotypes in living organisms. Experimental data and scientific publications following this technological advance- ment have rapidly accumulated in public databases. Meaningful analysis of currently avail- able data in genomic databases requires sophisticated computational tools and algorithms, and presents considerable challenges to molecular biologists without specialized training in bioinfor- matics. To study their phenotype of interest molecular biologists must prioritize large lists of poorly characterized genes generated in high-throughput experiments. To date, prioritization tools have primarily been designed to work with phenotypes of human diseases as defined by the genes known to be associated with those diseases. There is therefore a need for more prioritiza- tion tools for phenotypes which are not related with diseases generally or diseases with which no genes have yet been associated in particular. Chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) is a method of choice to study the gene regulation processes responsible for the expression of cellular phenotypes. Among publicly available computational pipelines for the processing of ChIP-Seq data, there is a lack of tools for the downstream analysis of composite motifs and preferred binding distances of the DNA binding proteins. -
Inhibition of SNW1 Association with Spliceosomal
Cancer Medicine Open Access ORIGINAL RESEARCH Inhibition of SNW1 association with spliceosomal proteins promotes apoptosis in breast cancer cells Naoki Sato1, Masao Maeda2, Mai Sugiyama2, Satoko Ito2, Toshinori Hyodo2, Akio Masuda3, Nobuyuki Tsunoda1, Toshio Kokuryo1, Michinari Hamaguchi2, Masato Nagino1 & Takeshi Senga2 1Department of Surgical Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan 2Division of Cancer Biology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan 3Division of Neurogenetics, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan Keywords Abstract Apoptosis, EFTUD2, PRPF8, RNA splicing, SNRNP200, SNW1 RNA splicing is a fundamental process for protein synthesis. Recent studies have reported that drugs that inhibit splicing have cytotoxic effects on various Correspondence tumor cell lines. In this report, we demonstrate that depletion of SNW1, a Takeshi Senga, 65 Tsurumai, Showa, Nagoya component of the spliceosome, induces apoptosis in breast cancer cells. Proteo- 466-8550, Japan. Tel: 81-52-744-2463; mics and biochemical analyses revealed that SNW1 directly associates with Fax: 81-52-744-2464; other spliceosome components, including EFTUD2 (Snu114) and SNRNP200 E-mail: [email protected] (Brr2). The SKIP region of SNW1 interacted with the N-terminus of EFTUD2 Funding Information as well as two independent regions in the C-terminus of SNRNP200. Similar to This research was funded by a grant from SNW1 depletion, knockdown of EFTUD2 increased the numbers of apoptotic the Ministry of Education, Culture, Sports, cells. Furthermore, we demonstrate that exogenous expression of either the Science and Technology of Japan SKIP region of SNW1 or the N-terminus region of EFTUD2 significantly pro- (Nanomedicine molecular science, 23107010. -
Genome-Wide Investigation of Cellular Functions for Trna Nucleus
Genome-wide Investigation of Cellular Functions for tRNA Nucleus- Cytoplasm Trafficking in the Yeast Saccharomyces cerevisiae DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Hui-Yi Chu Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2012 Dissertation Committee: Anita K. Hopper, Advisor Stephen Osmani Kurt Fredrick Jane Jackman Copyright by Hui-Yi Chu 2012 Abstract In eukaryotic cells tRNAs are transcribed in the nucleus and exported to the cytoplasm for their essential role in protein synthesis. This export event was thought to be unidirectional. Surprisingly, several lines of evidence showed that mature cytoplasmic tRNAs shuttle between nucleus and cytoplasm and their distribution is nutrient-dependent. This newly discovered tRNA retrograde process is conserved from yeast to vertebrates. Although how exactly the tRNA nuclear-cytoplasmic trafficking is regulated is still under investigation, previous studies identified several transporters involved in tRNA subcellular dynamics. At least three members of the β-importin family function in tRNA nuclear-cytoplasmic intracellular movement: (1) Los1 functions in both the tRNA primary export and re-export processes; (2) Mtr10, directly or indirectly, is responsible for the constitutive retrograde import of cytoplasmic tRNA to the nucleus; (3) Msn5 functions solely in the re-export process. In this thesis I focus on the physiological role(s) of the tRNA nuclear retrograde pathway. One possibility is that nuclear accumulation of cytoplasmic tRNA serves to modulate translation of particular transcripts. To test this hypothesis, I compared expression profiles from non-translating mRNAs and polyribosome-bound translating mRNAs collected from msn5Δ and mtr10Δ mutants and wild-type cells, in fed or acute amino acid starvation conditions.