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Effie Apostolou, Matthias Stadtfeld
The discovery of induced pluripotent stem cells (iPSCs) has solidified the concept of transcription factors as major players in controlling cell identity and provided a tractable tool to study how somatic cell identity can be dismantled and pluripotency established. A number of landmark studies have established hallmarks and roadmaps of iPSC formation by describing relative kinetics of transcriptional, protein and epigenetic changes, including alterations in DNA methylation and histone modifications. Recently, technological advancements such as single-cell analyses, high-resolution genome-wide chromatin assays and more efficient reprogramming systems have been used to challenge and refine our understanding of the reprogramming process...
June 16, 2018: Current Opinion in Genetics & Development
Evan E Santo, Jihye Paik
The rapid development of CRISPR technology is revolutionizing molecular approaches to the dissection of complex biological phenomena. Here we describe an alternative generally applicable implementation of the CRISPR-Cas9 system that allows for selective knockdown of extremely homologous genes. This strategy employs the lentiviral delivery of paired sgRNAs and nickase Cas9 (Cas9D10A) to achieve targeted deletion of splice junctions. This general strategy offers several advantages over standard single-guide exon-targeting CRISPR-Cas9 such as greatly reduced off-target effects, more restricted genomic editing, routine disruption of target gene mRNA expression and the ability to differentiate between closely related genes...
June 17, 2018: Gene
Christopher J Ricketts, Aguirre A De Cubas, Huihui Fan, Christof C Smith, Martin Lang, Ed Reznik, Reanne Bowlby, Ewan A Gibb, Rehan Akbani, Rameen Beroukhim, Donald P Bottaro, Toni K Choueiri, Richard A Gibbs, Andrew K Godwin, Scott Haake, A Ari Hakimi, Elizabeth P Henske, James J Hsieh, Thai H Ho, Rupa S Kanchi, Bhavani Krishnan, David J Kwiatkowski, Wembin Lui, Maria J Merino, Gordon B Mills, Jerome Myers, Michael L Nickerson, Victor E Reuter, Laura S Schmidt, C Simon Shelley, Hui Shen, Brian Shuch, Sabina Signoretti, Ramaprasad Srinivasan, Pheroze Tamboli, George Thomas, Benjamin G Vincent, Cathy D Vocke, David A Wheeler, Lixing Yang, William Y Kim, A Gordon Robertson, Paul T Spellman, W Kimryn Rathmell, W Marston Linehan
No abstract text is available yet for this article.
June 19, 2018: Cell Reports
Ryu Yashiro, Yukiko Murota, Kazumichi M Nishida, Haruna Yamashiro, Kaede Fujii, Asuka Ogai, Soichiro Yamanaka, Lumi Negishi, Haruhiko Siomi, Mikiko C Siomi
In Drosophila ovarian somatic cells (OSCs), Piwi represses transposons transcriptionally to maintain genome integrity. Piwi nuclear localization requires the N terminus and PIWI-interacting RNA (piRNA) loading of Piwi. However, the underlying mechanism remains unknown. Here, we show that Importinα (Impα) plays a pivotal role in Piwi nuclear localization and that Piwi has a bipartite nuclear localization signal (NLS). Impα2 and Impα3 are highly expressed in OSCs, whereas Impα1 is the least expressed. Loss of Impα2 or Impα3 forces Piwi to be cytoplasmic, which is rectified by overexpression of any Impα members...
June 19, 2018: Cell Reports
Andreas U Müller, Frank Imkamp, Eilika Weber-Ban
Mycobacteria exhibit two DNA damage response pathways: the LexA/RecA-dependent SOS response and a LexA/RecA-independent pathway. Using a combination of transcriptomics and genome-wide binding site analysis, we demonstrate that PafBC (proteasome accessory factor B and C), encoded in the Pup-proteasome system (PPS) gene locus, is the transcriptional regulator of the predominant LexA/RecA-independent pathway. Comparison of the resulting PafBC regulon with the DNA damage response of Mycobacterium smegmatis reveals that the majority of induced DNA repair genes are upregulated by PafBC...
June 19, 2018: Cell Reports
Sarah L Jaslow, Kyle D Gibbs, W Florian Fricke, Liuyang Wang, Kelly J Pittman, Mark K Mammel, Joshua T Thaden, Vance G Fowler, Gianna E Hammer, Johanna R Elfenbein, Dennis C Ko
Salmonella enterica is an important foodborne pathogen that uses secreted effector proteins to manipulate host pathways to facilitate survival and dissemination. Different S. enterica serovars cause disease syndromes ranging from gastroenteritis to typhoid fever and vary in their effector repertoire. We leveraged this natural diversity to identify stm2585, here designated sarA (Salmonella anti-inflammatory response activator), as a Salmonella effector that induces production of the anti-inflammatory cytokine IL-10...
June 19, 2018: Cell Reports
DarrenM Hutt, Salvatore Loguercio, Alexandre Rosa Campos, William E Balch
The advent of precision medicine for genetic diseases has been hampered by the large number of variants that cause familial and somatic disease, a complexity that is further confounded by the impact of genetic modifiers. To begin to understand differences in onset, progression and therapeutic response that exist among disease-causing variants, we present the proteomic variant approach (ProVarA), a proteomic method that integrates mass spectrometry with genomic tools to dissect the etiology of disease. To illustrate its value, we examined the impact of variation in cystic fibrosis (CF), where 2025 disease-associated mutations in the CF transmembrane conductance regulator (CFTR) gene have been annotated and where individual genotypes exhibit phenotypic heterogeneity and response to therapeutic intervention...
June 17, 2018: Journal of Molecular Biology
Soyeong Jun, Hyeonseob Lim, Hoon Jang, Wookjae Lee, Jinwoo Ahn, Ji Hyun Lee, Duhee Bang
CRISPR/Cas9 for genome editing requires delivery of a guide RNA sequence and donor DNA for targeted homologous recombination. Typically, single-stranded oligodeoxynucleotide, serving as the donor template, and a plasmid encoding guide RNA are delivered as two separate components. However, in the multiplexed generation of single nucleotide variants, this two-component delivery system is limited by difficulty of delivering a matched pair of sgRNA and donor DNA to the target cell. Here, we describe a novel co-delivery system called "sgR-DNA" that uses a linearized double-stranded DNA consisting of donor DNA component and a component encoding sgRNA...
June 20, 2018: ACS Synthetic Biology
Yufeng Lv, Wenhao Wei, Zhong Huang, Zhichao Chen, Yuan Fang, Lili Pan, Xueqiong Han, Zihai Xu
PURPOSE: The aim of this study was to develop a novel long non-coding RNA (lncRNA) expression signature to accurately predict early recurrence for patients with hepatocellular carcinoma (HCC) after curative resection. PATIENTS AND METHODS: Using expression profiles downloaded from The Cancer Genome Atlas database, we identified multiple lncRNAs with differential expression between early recurrence (ER) group and non-early recurrence (non-ER) group of HCC. Least absolute shrinkage and selection operator (LASSO) for logistic regression models were used to develop a lncRNA-based classifier for predicting ER in the training set...
June 20, 2018: Hepatology Research: the Official Journal of the Japan Society of Hepatology
Samuel M D Seaver, Claudia Lerma-Ortiz, Neal Conrad, Arman Mikaili, Avinash Sreedasyam, Andrew D Hanson, Christopher S Henry
Genome-scale metabolic reconstructions help understand and engineer metabolism. Next-Gen sequencing technologies are delivering genomes and transcriptomes for an ever-widening range of plants. While such omic data can, in principle, be used to compare metabolic networks in different species, organs, and environmental conditions, these comparisons require a standardized framework for metabolic network reconstruction from transcript data. We previously introduced the PlantSEED as a framework covering primary metabolism for ten species...
June 20, 2018: Plant Journal: for Cell and Molecular Biology
Sébastien Wielgoss, Francesca Fiegna, Olaya Rendueles, Yuen-Tsu N Yu, Gregory J Velicer
Genetically similar cells of the soil bacterium Myxococcus xanthus cooperate at multiple social behaviours, including motility and multicellular development. Another social interaction in this species is outer-membrane exchange (OME), a behaviour of unknown primary benefit in which cells displaying closely related variants of the outer-membrane protein TraA transiently fuse and exchange membrane contents. Functionally incompatible TraA variants do not mediate OME, which led to the proposal that TraA incompatibilities determine patterns of intercellular cooperation in nature, but how this might occur remains unclear...
June 20, 2018: Molecular Ecology
Rhiannon Kundu, Robin Knight, Meenakshi Dunga, Mark Peakman
Coxsackie B Virus (CBV) infection has been linked to the aetiology of type 1 diabetes (T1D) and vaccination has been proposed as prophylaxis for disease prevention. Serum neutralising antibodies and the presence of viral protein and RNA in tissues have been common tools to examine this potential disease relationship, whilst the role of anti-CBV cytotoxic T cell responses and their targets have not been studied. To address this knowledge gap, we augmented conventional HLA-binding predictive algorithm-based epitope discovery by cross-referencing epitopes with sites of positive natural selection within the CBV3 viral genome, identified using mixed effects models of evolution...
2018: PloS One
Cha Gon Lee, Jeehun Lee, Munhyang Lee
Genetic heterogeneity of common genetic generalized epilepsy syndromes is frequently considered. The present study conducted a focused analysis of potential candidate or susceptibility genes for common genetic generalized epilepsy syndromes using multi-gene panel testing with next-generation sequencing. This study included patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We identified pathogenic variants according to the American College of Medical Genetics and Genomics guidelines and identified susceptibility variants using case-control association analyses and family analyses for familial cases...
2018: PloS One
Iván Torres, Antonio Parra, José M Moreno, Walter Durka
In Mediterranean ecosystems, climate change is projected to increase fire danger and summer drought, thus reducing post-fire recruitment of obligate seeder species, and possibly affecting the population genetic structure. We performed a genome-wide genetic marker study, using AFLP markers, on individuals from one Central Spain population of the obligate post-fire seeder Cistus ladanifer L. that established after experimental fire and survived during four subsequent years under simulated drought implemented with a rainout shelter system...
2018: PloS One
Laura Flatau, Markus Reitt, Gunnar Duttge, Christian Lenk, Barbara Zoll, Wolfgang Poser, Alexandra Weber, Urs Heilbronner, Marcella Rietschel, Jana Strohmaier, Rebekka Kesberg, Jonas Nagel, Thomas G Schulze
In clinical practice and in research, there is an ongoing debate on how to return incidental and secondary findings of genetic tests to patients and research participants. Previous investigations have found that most of the people most of the time are in favor of full disclosure of results. Yet, the option to reject disclosure, based on the so-called right not to know, can be valuable especially for some vulnerable subgroups of recipients. In the present study we investigated variations in informational preferences in the context of genetic testing in a large and diverse German sample...
2018: PloS One
Marion McElwee, Swetha Vijayakrishnan, Frazer Rixon, David Bhella
Herpesviruses include many important human pathogens such as herpes simplex virus, cytomegalovirus, varicella-zoster virus, and the oncogenic Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus. Herpes virions contain a large icosahedral capsid that has a portal at a unique 5-fold vertex, similar to that seen in the tailed bacteriophages. The portal is a molecular motor through which the viral genome enters the capsid during virion morphogenesis. The genome also exits the capsid through the portal-vertex when it is injected through the nuclear pore into the nucleus of a new host cell to initiate infection...
June 20, 2018: PLoS Biology
Andreas Porodko, Ana Cirnski, Drazen Petrov, Teresa Raab, Melanie Paireder, Bettina Mayer, Daniel Maresch, Lisa Nika, Martin L Biniossek, Patrick Gallois, Oliver Schilling, Chris Oostenbrink, Marko Novinec, Lukas Mach
The genome of the model plant Arabidopsis thaliana encodes three paralogues of the papainlike cysteine proteinase cathepsin B (AtCathB1, AtCathB2 and AtCathB3), whose individual functions are still largely unknown. Here we show that a mutated splice site causes severe truncations of the AtCathB1 polypeptide, rendering it catalytically incompetent. By contrast, AtCathB2 and AtCathB3 are effective proteases which display comparable hydrolytic properties and share most of their substrate specificities. Site-directed mutagenesis experiments demonstrated that a single amino acid substitution (Gly336→Glu) is sufficient to confer AtCathB2 with the capacity to tolerate arginine in its specificity-determining S2 subsite, which is otherwise a hallmark of AtCathB3-mediated cleavages...
June 1, 2018: Biological Chemistry
Gareth Bloomfield
Sex in social amoebae (or dictyostelids) has a number of striking features. Dictyostelid zygotes do not proliferate but grow to a large size by feeding on other cells of the same species, each zygote ultimately forming a walled structure called a macrocyst. The diploid macrocyst nucleus undergoes meiosis, after which a single meiotic product survives to restart haploid vegetative growth. Meiotic recombination is generally initiated by the Spo11 enzyme, which introduces DNA double-strand breaks. Uniquely, as far as is known among sexual eukaryotes, dictyostelids lack a SPO11 gene...
June 20, 2018: Annual Review of Microbiology
Malcolm Grant, John Paul Maytum
No abstract text is available yet for this article.
June 20, 2018: Personalized Medicine
Tslil Gabrieli, Hila Sharim, Gil Nifker, Jonathan Jeffet, Tamar Shahal, Rani Arielly, Michal Levy-Sakin, Lily Hoch, Nissim Arbib, Yael Michaeli, Yuval Ebenstein
The epigenetic mark 5-hydroxymethylcytosine (5-hmC) is a distinct product of active DNA demethylation that is linked to gene regulation, development, and disease. In particular, 5-hmC levels dramatically decline in many cancers, potentially serving as an epigenetic biomarker. The noise associated with next-generation 5-hmC sequencing hinders reliable analysis of low 5-hmC containing tissues such as blood and malignant tumors. Additionally, genome-wide 5-hmC profiles generated by short-read sequencing are limited in providing long-range epigenetic information relevant to highly variable genomic regions, such as the 3...
June 20, 2018: ACS Nano
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