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Food for Thought: Should We Analyze a Cancer Cell as a Biological Mechanism or as a Biological Computer?

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JOURNAL OF THORACIC ONCOLOGY 2017年第1期12卷 S1148-S1148页

作者： Vrbica, Zarko Jakopovic, Marko Univ Dubrovnik Dubrovnik Croatia Univ Zagreb Sch Med Zagreb Croatia

P3.01-047

关键词： Cancer biology non-coding dna Cancer genomic

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Reducing GWAS Complexity

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CELL CYCLE 2016年第1期15卷 22-24页

作者： Hazelett, Dennis J. Conti, David V. Han, Ying Al Olama, Ali Amin Easton, Doug Eeles, Rosalind A. Kote-Jarai, Zsofia Haiman, Christopher A. Coetzee, Gerhard A. Cedars Sinai Med Ctr Bioinformat & Computat Biol Res Ctr Biomed Sci Los Angeles CA 90048 USA USC Norris Cotton Canc Ctr Dept Prevent Med Los Angeles CA USA USC Norris Cotton Canc Ctr Dept Urol Los Angeles CA USA Univ Cambridge Ctr Canc Genet Epidemiol Div Genet & Epidemiol Cambridge England Inst Canc Res London SW3 6JB England Royal Marsden NHS Fdn Trust London England USC Norris Cotton Canc Ctr Keck Sch Med Microbiol & Prevent Med NTT 64111441 Eastlake Ave Los Angeles Los Angeles CA 90089 USA

Genome-wide association studies (GWAS) have revealed numerous genomic 'hits' associated with complex phenotypes. In most cases these hits, along with surrogate genetic variation as measure by numerous single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium, are not in coding genes making assignment of functionality or causality intractable. Here we propose that fine-mapping along with the matching of risk SNPs at chromatin biofeatures lessen this complexity by reducing the number of candidate functional/causal SNPs. For example, we show here that only on average 2 SNPs per prostate cancer risk locus are likely candidates for functionality/causality;we further propose that this manageable number should be taken forward in mechanistic studies. The candidate SNPs can be looked up for each prostate cancer risk region in 2 recent publications in 2015(1,2) from our groups.

关键词： GWAS SNP Cancer chromatin non-coding dna enhancer fine-mapping

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Genomic Alterations of non-coding Regions Underlie Human Cancer: Lessons from T-ALL

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TRENDS IN MOLECULAR MEDICINE 2016年第12期22卷 1035-1046页

作者： Rivera-Reyes, Adrian Hayer, Katharina E. Bassing, Craig H. Childrens Hosp Philadelphia Ctr Childhood Canc Res Dept Pathol & Lab Med Div Canc Pathobiol Philadelphia PA 19104 USA Univ Penn Perelman Sch Med Cell & Mol Biol Grad Grp Dept Pathol & Lab MedAbramson Family Canc Res In Philadelphia PA 19104 USA

It has been appreciated for decades that somatic genomic alterations that change coding sequences of proto-oncogenes, translocate enhancers/promoters near proto-oncogenes, or create fusion oncogenes can drive cancer by inducing oncogenic activities. An explosion of genome-wide technologies over the past decade has fueled discoveries of the roles of three-dimensional chromosome structure and powerful cis-acting elements (super-enhancers) in regulating gene transcription. In recent years, studies of human T cell acute lymphoblastic leukemia (T-ALL) using genome-wide technologies have provided paradigms for how non-coding genomic region alterations can disrupt 3D chromosome architecture or establish super-enhancers to activate oncogenic transcription of proto-oncogenes. These studies raise important issues to consider with the objective of leveraging basic knowledge into new diagnostic and therapeutic opportunities for cancer patients.

关键词： GENOMICS non-coding RNA non-coding dna ONCOGENES ADULT T-cell leukemia GENETIC transcription regulation TREATMENT

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Systematic mapping of functional enhancer-promoter connections with CRISPR interference

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SCIENCE 2016年第6313期354卷 769-773页

作者： Fulco, Charles P. Munschauer, Mathias Anyoha, Rockwell Munson, Glen Grossman, Sharon R. Perez, Elizabeth M. Kane, Michael Cleary, Brian Lander, Eric S. Engreitz, Jesse M. Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Dept Syst Biol Boston MA 02115 USA MIT Div Hlth Sci & Technol Cambridge MA 02139 USA MIT Dept Biol 77 Massachusetts Ave Cambridge MA 02139 USA MIT Computat & Syst Biol Program 77 Massachusetts Ave Cambridge MA 02139 USA

Gene expression in mammals is regulated by noncoding elements that can affect physiology and disease, yet the functions and target genes of most noncoding elements remain unknown. We present a high-throughput approach that uses clustered regularly interspaced short palindromic repeats (CRISPR) interference (CRISPRi) to discover regulatory elements and identify their target genes. We assess >1 megabase of sequence in the vicinity of two essential transcription factors, MYC and GATA1, and identify nine distal enhancers that control gene expression and cellular proliferation. Quantitative features of chromatin state and chromosome conformation distinguish the seven enhancers that regulate MYC from other elements that do not, suggesting a strategy for predicting enhancer-promoter connectivity. This CRISPRi-based approach can be applied to dissect transcriptional networks and interpret the contributions of noncoding genetic variation to human disease.

关键词： CRISPRS (Genetics) GENE expression non-coding dna TRANSCRIPTION factors CELL proliferation CHROMATIN CHROMOSOMES

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Beyond the exome: the role of non-coding somatic mutations in cancer

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ANNALS OF ONCOLOGY 2016年第2期27卷 240-248页

作者： Piraino, S. W. Furney, S. J. Univ Coll Dublin Sch Med Conway Inst Biomol & Biomed Res Dublin 4 Ireland

The comprehensive identification of mutations contributing to the development of cancer is a priority of large cancer sequencing projects. To date, most studies have scrutinized mutations in coding regions of the genome, but several recent discoveries, including the identification of recurrent somatic mutations in the TERT promoter in multiple cancer types, support the idea that mutations in non-coding regions are also important in tumour development. Furthermore, analysis of whole-genome sequencing data from tumours has elucidated novel mutational patterns and processes etched into cancer genomes. Here, we present an overview of insights gleaned from the analysis of mutations from sequenced cancer genomes. We then review the mechanisms by which non-coding mutations can play a role in cancer. Finally, we discuss recent efforts aimed at identifying non-coding driver mutations, as well as the unique challenges that the analysis of non-coding mutations present in contrast to the identification of driver mutations in coding regions.

关键词： whole-genome sequencing driver mutations non-coding dna mutational signatures

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iDHS-EL: identifying dnase I hypersensitive sites by fusing three different modes of pseudo nucleotide composition into an ensemble learning framework

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BIOINFORMATICS 2016年第16期32卷 2411-2418页

作者： Liu, Bin Long, Ren Chou, Kuo-Chen Harbin Inst Technol Shenzhen Grad Sch Sch Comp Sci & Technol Shenzhen 518055 Guangdong Peoples R China Harbin Inst Technol Shenzhen Grad Sch Key Lab Network Oriented Intelligent Computat Shenzhen 518055 Guangdong Peoples R China Gordon Life Sci Inst Belmont MA 02478 USA King Abdulaziz Univ CEGMR Jeddah 21589 Saudi Arabia

Motivation: Regulatory dna elements are associated with dnase I hypersensitive sites (DHSs). Accordingly, identification of DHSs will provide useful insights for in-depth investigation into the function of noncoding genomic regions. Results: In this study, using the strategy of ensemble learning framework, we proposed a new predictor called iDHS-EL for identifying the location of DHS in human genome. It was formed by fusing three individual Random Forest (RF) classifiers into an ensemble predictor. The three RF operators were respectively based on the three special modes of the general pseudo nucleotide composition (PseKNC): (i) kmer, (ii) reverse complement kmer and (iii) pseudo dinucleotide composition. It has been demonstrated that the new predictor remarkably outperforms the relevant state-of-the-art methods in both accuracy and stability.

关键词： NUCLEOTIDES dna non-coding dna HUMAN genome CHROMATIN TRANSCRIPTION factors

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High-resolution interrogation of functional elements in the noncoding genome

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SCIENCE 2016年第6307期353卷 1545-1549页

作者： Sanjana, Neville E. Wright, Jason Zheng, Kaijie Shalem, Ophir Fontanillas, Pierre Joung, Julia Cheng, Christine Regev, Aviv Zhang, Feng Broad Inst MIT & Harvard 7 Cambridge Ctr Cambridge MA 02142 USA MIT Dept Biol Engn Dept Brain & Cognit Sci McGovern Inst Brain Res Cambridge MA 02139 USA MIT Dept Biol Howard Hughes Med Inst David H Koch Inst Integrat Canc Biol 77 Massachusetts Ave Cambridge MA 02142 USA NYU New York Genome Ctr 550 1St Ave New York NY 10012 USA NYU Dept Biol 550 1St Ave New York NY 10012 USA

The noncoding genome affects gene regulation and disease, yet we lack tools for rapid identification and manipulation of noncoding elements. We developed a CRISPR screen using similar to 18,000 single guide RNAs targeting >700 kilobases surrounding the genes NF1, NF2, and CUL3, which are involved in BRAF inhibitor resistance in melanoma. We find that noncoding locations that modulate drug resistance also harbor predictive hallmarks of noncoding function. With a subset of regions at the CUL3 locus, we demonstrate that engineered mutations alter transcription factor occupancy and long-range and local epigenetic environments, implicating these sites in gene regulation and chemotherapeutic resistance. Through our expansion of the potential of pooled CRISPR screens, we provide tools for genomic discovery and for elucidating biologically relevant mechanisms of gene regulation.

关键词： non-coding dna GENETIC regulation CRISPRS (Genetics) BRAF genes MELANOMA DRUG resistance in cancer cells MUTATION (Biology)

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ConsPred: a rule-based (re-)annotation framework for prokaryotic genomes

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BIOINFORMATICS 2016年第21期32卷 3327-3329页

作者： Weinmaier, Thomas Platzer, Alexander Frank, Jeroen Hellinger, Hans-Jorg Tischler, Patrick Rattei, Thomas Univ Vienna Dept Microbiol & Ecosyst Sci Vienna Austria Radboud Univ Nijmegen Dept Microbiol Nijmegen Netherlands Tech Univ Munich Dept Genome Oriented Bioinformat Freising Weihenstephan Germany

Motivation: The rapidly growing number of available prokaryotic genome sequences requires fully automated and high-quality software solutions for their initial and re-annotation. Here we present ConsPred, a prokaryotic genome annotation framework that performs intrinsic gene predictions, homology searches, predictions of non-coding genes as well as CRISPR repeats and integrates all evidence into a consensus annotation. ConsPred achieves comprehensive, high-quality annotations based on rules and priorities, similar to decision-making in manual curation and avoids conflicting predictions. Parameters controlling the annotation process are configurable by the user. ConsPred has been used in the institutions of the authors for longer than 5 years and can easily be extended and adapted to specific needs. Summary:The ConsPred algorithm for producing a consensus from the varying scores of multiple gene prediction programs approaches manual curation in accuracy. Its rule-based approach for choosing final predictions avoids overriding previous manual curations.

关键词： PROKARYOTIC genomes dna sequencing COMPUTER software non-coding dna CRISPRS (Genetics)

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(Dicer)phering roles of microRNA in platelets

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BLOOD 2016年第14期127卷 1733-1734页

作者： Boilard, Eric Belleannee, Clemence Ctr Hosp Univ Quebec Ctr Rech Quebec City PQ Canada

The article reports that noncoding RNAs precisely regulate the messenger RNA (mRNA) profile in platelets. It states how interfering in this process using genetically engineered mice affects hemostatic and thrombotic functions of platelets. The reduction of miRNA expression in the absence of Dicer1 is reported to suggest that the miRNAs are mainly generated before PF4 activation, highlighting the stability of miRNA in maturing megakaryocytes and platelets.

关键词： MICRORNA RNA non-coding dna BLOOD platelets MEGAKARYOCYTES

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Tools4miRs-one place to gather all the tools for miRNA analysis

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BIOINFORMATICS 2016年第17期32卷 2722-2724页

作者： Lukasik, Anna Wojcikowski, Maciej Zielenkiewicz, Piotr Polish Acad Sci Inst Biochem & Biophys PL-02106 Warsaw Poland Univ Warsaw Inst Expt Plant Biol & Biotechnol Dept Syst Biol PL-02096 Warsaw Poland

MiRNAs are short, non-coding molecules that negatively regulate gene expression and thereby play several important roles in living organisms. Dozens of computational methods for miRNA-related research have been developed, which greatly differ in various aspects. The substantial availability of difficult-to-compare approaches makes it challenging for the user to select a proper tool and prompts the need for a solution that will collect and categorize all the methods. Here, we present tools4miRs, the first platform that gathers currently more than 160 methods for broadly defined miRNA analysis. The collected tools are classified into several general and more detailed categories in which the users can additionally filter the available methods according to their specific research needs, capabilities and preferences. Tools4miRs is also a web-based target prediction meta-server that incorporates user-designated target prediction methods into the analysis of user-provided data.

关键词： MICRORNA GENE expression GENETIC engineering non-coding dna COMPUTATIONAL biology MICROBIOLOGY

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