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Genome Research

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https://www.readbyqxmd.com/read/28916540/massive-reshaping-of-genome-nuclear-lamina-interactions-during-oncogene-induced-senescence
#1
Christelle Lenain, Carolyn A de Graaf, Ludo Pagie, Nils L Visser, Marcel de Haas, Sandra S de Vries, Daniel Peric-Hupkes, Bas van Steensel, Daniel S Peeper
Cellular senescence is a mechanism that virtually irreversibly suppresses the proliferative capacity of cells in response to various stress signals. This includes the expression of activated oncogenes, which causes Oncogene-Induced Senescence (OIS). A body of evidence points to the involvement in OIS of chromatin reorganization, including the formation of senescence-associated heterochromatic foci (SAHF). The nuclear lamina (NL) is an important contributor to genome organization and has been implicated in cellular senescence and organismal aging...
September 15, 2017: Genome Research
https://www.readbyqxmd.com/read/28916539/comparative-analysis-of-alternative-polyadenylation-in-s-cerevisiae-and-s-pombe
#2
Xiaochuan Liu, Mainul Hoque, Marc Larochelle, Jean-François Lemay, Nathan Yurko, James L Manley, François Bachand, Bin Tian
Alternative polyadenylation (APA) is a widespread mechanism that generates mRNA isoforms with distinct properties. Here we have systematically mapped and compared cleavage and polyadenylation sites (PASs) in two yeast species, S. cerevisiae and S. pombe Although >80% of the mRNA genes in each species were found to display APA, S. pombe showed greater 3' UTR size differences among APA isoforms than did S. cerevisiae PASs in different locations of gene are surrounded with distinct sequences in both species and are often associated with motifs involved in the Nrd1-Nab3-Sen1 termination pathway...
September 15, 2017: Genome Research
https://www.readbyqxmd.com/read/28912372/genome-wide-maps-of-alkylation-damage-repair-and-mutagenesis-in-yeast-reveal-mechanisms-of-mutational-heterogeneity
#3
Peng Mao, Alexander J Brown, Ewa P Malc, Piotr A Mieczkowski, Michael J Smerdon, Steven A Roberts, John J Wyrick
DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome-depleted regions, and slower repair and higher mutation density within strongly positioned nucleosomes...
September 14, 2017: Genome Research
https://www.readbyqxmd.com/read/28904015/sasquatch-predicting-the-impact-of-regulatory-snps-on-transcription-factor-binding-from-cell-and-tissue-specific-dnase-footprints
#4
Ron Schwessinger, Maria C Suciu, Simon J McGowan, Jelena Telenius, Stephen Taylor, Doug R Higgs, Jim R Hughes
In the era of genome-wide association studies (GWAS) and personalized medicine, predicting the impact of single nucleotide polymorphisms (SNPs) in regulatory elements is an important goal. Current approaches to determine the potential of regulatory SNPs depend on inadequate knowledge of cell-specific DNA binding motifs. Here, we present Sasquatch, a new computational approach that uses DNase footprint data to estimate and visualize the effects of noncoding variants on transcription factor binding. Sasquatch performs a comprehensive k-mer-based analysis of DNase footprints to determine any k-mer's potential for protein binding in a specific cell type and how this may be changed by sequence variants...
September 13, 2017: Genome Research
https://www.readbyqxmd.com/read/28904014/redundant-and-incoherent-regulations-of-multiple-phenotypes-suggest-micrornas-role-in-stability-control
#5
Zhongqi Liufu, Yixin Zhao, Li Guo, Guangxia Miao, Juan Xiao, Yang Lyu, Yuxin Chen, Suhua Shi, Tian Tang, Chung-I Wu
Each microRNA (miRNA) represses a web of target genes and, through them, controls multiple phenotypes. The difficulties inherent in such controls cast doubt on how effective miRNAs are in driving phenotypic changes. A "simple regulation" model posits "one target-one phenotype" control under which most targeting is nonfunctional. In an alternative "coordinate regulation" model, multiple targets are assumed to control the same phenotypes coherently, and most targeting is functional. Both models have some empirical support but pose different conceptual challenges...
September 13, 2017: Genome Research
https://www.readbyqxmd.com/read/28904013/integrative-analysis-of-rna-polymerase-ii-and-transcriptional-dynamics-upon-myc-activation
#6
Stefano de Pretis, Theresia R Kress, Marco J Morelli, Arianna Sabò, Chiara Locarno, Alessandro Verrecchia, Mirko Doni, Stefano Campaner, Bruno Amati, Mattia Pelizzola
Overexpression of the MYC transcription factor causes its widespread interaction with regulatory elements in the genome but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of transcription and mRNA dynamics following MYC activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing, and mathematical modeling...
September 13, 2017: Genome Research
https://www.readbyqxmd.com/read/28904012/identification-of-a-core-tp53-transcriptional-program-with-highly-distributed-tumor-suppressive-activity
#7
Zdenek Andrysik, Matthew D Galbraith, Anna L Guarnieri, Sara Zaccara, Kelly D Sullivan, Ahwan Pandey, Morgan MacBeth, Alberto Inga, Joaquín M Espinosa
The tumor suppressor TP53 is the most frequently mutated gene product in human cancer. Close to half of all solid tumors carry inactivating mutations in the TP53 gene, while in the remaining cases, TP53 activity is abrogated by other oncogenic events, such as hyperactivation of its endogenous repressors MDM2 or MDM4. Despite identification of hundreds of genes regulated by this transcription factor, it remains unclear which direct target genes and downstream pathways are essential for the tumor suppressive function of TP53...
September 13, 2017: Genome Research
https://www.readbyqxmd.com/read/28887402/detection-of-long-repeat-expansions-from-pcr-free-whole-genome-sequence-data
#8
Egor Dolzhenko, Joke J F A van Vugt, Richard J Shaw, Mitchell A Bekritsky, Marka van Blitterswijk, Giuseppe Narzisi, Subramanian S Ajay, Vani Rajan, Bryan Lajoie, Nathan H Johnson, Zoya Kingsbury, Sean J Humphray, Raymond D Schellevis, William J Brands, Matt Baker, Rosa Rademakers, Maarten Kooyman, Gijs H P Tazelaar, Michael A van Es, Russell McLaughlin, William Sproviero, Aleksey Shatunov, Ashley Jones, Ahmad Al Khleifat, Alan Pittman, Sarah Morgan, Orla Hardiman, Ammar Al-Chalabi, Chris Shaw, Bradley Smith, Edmund J Neo, Karren Morrison, Pam Shaw, Catherine Reeves, Lara Winterkorn, Nancy S Wexler, David E Housman, Christopher W Ng, Alina L Li, Ryan J Taft, Leonard H van den Berg, David R Bentley, Jan H Veldink, Michael A Eberle
Identifying large expansions of short tandem repeats (STRs) such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step towards integrating WGS into precision medicine. We have developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length...
September 8, 2017: Genome Research
https://www.readbyqxmd.com/read/28877962/toward-the-human-cellular-micrornaome
#9
Matthew N McCall, Min-Sik Kim, Mohammed Adil, Arun H Patil, Yin Lu, Christopher J Mitchell, Pamela Leal-Rojas, Jinchong Xu, Manoj Kumar, Valina L Dawson, Ted M Dawson, Alexander S Baras, Avi Z Rosenberg, Dan E Arking, Kathleen H Burns, Akhilesh Pandey, Marc K Halushka
MicroRNAs are short RNAs that serve as regulators of gene expression and are essential components of normal development as well as modulators of disease. MicroRNAs generally act cell-autonomously, and thus their localization to specific cell types is needed to guide our understanding of microRNA activity. Current tissue-level data have caused considerable confusion, and comprehensive cell-level data do not yet exist. Here, we establish the landscape of human cell-specific microRNA expression. This project evaluated 8 billion small RNA-seq reads from 46 primary cell types, 42 cancer or immortalized cell lines, and 26 tissues...
September 6, 2017: Genome Research
https://www.readbyqxmd.com/read/28874398/solid-phase-reverse-transfection-for-intracellular-delivery-of-functionally-active-proteins
#10
Ruben Bulkescher, Vytaute Starkuviene, Holger Erfle
Delivery of large and functionally active biomolecules across cell membranes presents a challenge in cell biological experimentation. For this purpose, we developed a novel solid-phase reverse transfection method that is suitable for the intracellular delivery of proteins into mammalian cells with preservation of their function. We show results for diverse application areas of the method, ranging from antibody-mediated inhibition of protein function to CRISPR/Cas9-based gene editing in living cells. Our method enables prefabrication of "ready to transfect" substrates carrying diverse proteins...
September 5, 2017: Genome Research
https://www.readbyqxmd.com/read/28864459/rna-editing-in-bacteria-recodes-multiple-proteins-and-regulates-an-evolutionarily-conserved-toxin-antitoxin-system
#11
Dan Bar-Yaacov, Ernest Mordret, Ruth Towers, Tammy Biniashvili, Clara Soyris, Schraga Schwartz, Orna Dahan, Yitzhak Pilpel
Adenosine (A) to inosine (I) RNA editing is widespread in eukaryotes. In prokaryotes, however, A-to-I RNA editing was only reported to occur in tRNAs but not in protein-coding genes. By comparing DNA and RNA sequences of Escherichia coli, we show for the first time that A-to-I editing occurs also in prokaryotic mRNAs and has the potential to affect the translated proteins and cell physiology. We found 15 novel A-to-I editing events, of which 12 occurred within known protein-coding genes where they always recode a tyrosine (TAC) into a cysteine (TGC) codon...
September 1, 2017: Genome Research
https://www.readbyqxmd.com/read/28864458/optimizing-genomic-medicine-in-epilepsy-through-a-gene-customized-approach-to-missense-variant-interpretation
#12
Joshua Traynelis, Michael Silk, Quanli Wang, Samuel F Berkovic, Liping Liu, David B Ascher, David J Balding, Slavé Petrovski
Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes...
September 1, 2017: Genome Research
https://www.readbyqxmd.com/read/28855263/an-atlas-of-alternative-splicing-profiles-and-functional-associations-reveals-new-regulatory-programs-and-genes-that-simultaneously-express-multiple-major-isoforms
#13
Javier Tapial, Kevin C H Ha, Timothy Sterne-Weiler, Andre Gohr, Ulrich Braunschweig, Antonio Hermoso-Pulido, Mathieu Quesnel-Vallières, Jon Permanyer, Reza Sodaei, Yamile Marquez, Luca Cozzuto, Xinchen Wang, Melisa Gómez-Velázquez, Teresa Rayon, Miguel Manzanares, Julia Ponomarenko, Benjamin Blencowe, Manuel Irimia
Alternative splicing (AS) generates remarkable regulatory and proteomic complexity in metazoans. However, the functions of most AS events are not known and programs of regulated splicing remain to be identified. To address these challenges, we describe the Vertebrate Alternative Splicing and Transcription Database (VastDB), the largest resource of genome-wide, quantitative profiles of AS events assembled to date. VastDB provides readily accessible quantitative information on the inclusion levels and functional associations of AS events detected in RNA-seq data from diverse vertebrate cell and tissue types, as well as developmental stages...
August 30, 2017: Genome Research
https://www.readbyqxmd.com/read/28855262/transposable-elements-are-the-primary-source-of-novelty-in-primate-gene-regulation
#14
Marco Trizzino, YoSon Park, Marcia Holsbach-Beltrame, Katherine Aracena, Katelyn Mika, Minal Caliskan, George H Perry, Vincent J Lynch, Christopher D Brown
Gene regulation shapes the evolution of phenotypic diversity. We investigated the evolution of liver promoters and enhancers in six primate species using ChIP-seq (H3K27ac and H3K4me1) to profile cis-regulatory elements (CREs) and using RNA-seq to characterize gene expression in the same individuals. To quantify regulatory divergence, we compared CRE activity across species by testing differential ChIP-seq read depths directly measured for orthologous sequences. We show that the primate regulatory landscape is largely conserved across the lineage, with 63% of the tested human liver CREs showing similar activity across species...
August 30, 2017: Genome Research
https://www.readbyqxmd.com/read/28855261/detection-of-structural-mosaicism-from-targeted-and-whole-genome-sequencing-data
#15
Daniel A King, Alejandro Sifrim, Tomas W Fitzgerald, Raheleh Rahbari, Emma Hobson, Tessa Homfray, Sahar Mansour, Sarju G Mehta, Mohammed Shehla, Susan E Tomkins, Pradeep C Vasudevan, Matthew E Hurles
Structural mosaic abnormalities are large post-zygotic mutations present in a subset of cells and have been implicated in developmental disorders and cancer. Such mutations have been conventionally assessed in clinical diagnostics using cytogenetic or microarray testing. Modern disease studies rely heavily on exome sequencing, yet an adequate method for the detection of structural mosaicism using targeted sequencing data is lacking. Here, we present a method, called MrMosaic, to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next-generation sequencing data...
August 30, 2017: Genome Research
https://www.readbyqxmd.com/read/28855260/hicrep-assessing-the-reproducibility-of-hi-c-data-using-a-stratum-adjusted-correlation-coefficient
#16
Tao Yang, Feipeng Zhang, Galip Gurkan Yardimci, Fan Song, Ross C Hardison, William Stafford Noble, Feng Yue, Qunhua Li
Hi-C is a powerful technology for studying genome-wide chromatin interactions. However, current methods for assessing Hi-C data reproducibility can produce misleading results because they ignore spatial features in Hi-C data, such as domain structure and distance dependence. We present HiCRep, a framework for assessing the reproducibility of Hi-C data that systematically accounts for these features. In particular, we introduce a novel similarity measure, the stratum adjusted correlation coefficient (SCC), for quantifying the similarity between Hi-C interaction matrices...
August 30, 2017: Genome Research
https://www.readbyqxmd.com/read/28855259/the-mobile-element-locator-tool-melt-population-scale-mobile-element-discovery-and-biology
#17
Eugene J Gardner, Vincent K Lam, Daniel N Harris, Nelson T Chuang, Emma C Scott, William S Pittard, Ryan E Mills, Scott E Devine
Mobile element insertions (MEIs) represent ~25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale...
August 30, 2017: Genome Research
https://www.readbyqxmd.com/read/28847918/discovering-novel-pharmacogenomic-biomarkers-by-imputing-drug-response-in-cancer-patients-from-large-genomics-studies
#18
Paul Geeleher, Zhenyu Zhang, Fan Wang, Robert F Gruener, Aritro Nath, Gladys Morrison, Steven Bhutra, Robert L Grossman, R Stephanie Huang
Obtaining accurate drug response data in large cohorts of cancer patients is very challenging; thus, most cancer pharmacogenomics discovery is conducted in preclinical studies, typically using cell lines and mouse models. However, these platforms suffer from serious limitations, including small sample sizes. Here, we have developed a novel computational method that allows us to impute drug response in very large clinical cancer genomics data sets, such as The Cancer Genome Atlas (TCGA). The approach works by creating statistical models relating gene expression to drug response in large panels of cancer cell lines and applying these models to tumor gene expression data in the clinical data sets (e...
August 28, 2017: Genome Research
https://www.readbyqxmd.com/read/28784836/detecting-ancient-positive-selection-in-humans-using-extended-lineage-sorting
#19
Stéphane Peyrégne, Michael James Boyle, Michael Dannemann, Kay Prüfer
Natural selection that affected modern humans early in their evolution has likely shaped some of the traits that set present-day humans apart from their closest extinct and living relatives. The ability to detect ancient natural selection in the human genome could provide insights into the molecular basis for these human-specific traits. Here, we introduce a method for detecting ancient selective sweeps by scanning for extended genomic regions where our closest extinct relatives, Neandertals and Denisovans, fall outside of the present-day human variation...
July 18, 2017: Genome Research
https://www.readbyqxmd.com/read/28720578/systematic-longitudinal-survey-of-invasive-escherichia-coli-in-england-demonstrates-a-stable-population-structure-only-transiently-disturbed-by-the-emergence-of-st131
#20
Teemu Kallonen, Hayley J Brodrick, Simon R Harris, Jukka Corander, Nicholas M Brown, Veronique Martin, Sharon J Peacock, Julian Parkhill
Escherichia coli associated with urinary tract infections and bacteremia has been intensively investigated, including recent work focusing on the virulent, globally disseminated, multidrug-resistant lineage ST131. To contextualize ST131 within the broader E. coli population associated with disease, we used genomics to analyze a systematic 11-yr hospital-based survey of E. coli associated with bacteremia using isolates collected from across England by the British Society for Antimicrobial Chemotherapy and from the Cambridge University Hospitals NHS Foundation Trust...
July 18, 2017: Genome Research
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