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Designer chromatin

Chongsheng He, Simone Sidoli, Robert Warneford-Thomson, Deirdre C Tatomer, Jeremy E Wilusz, Benjamin A Garcia, Roberto Bonasio
Interactions between noncoding RNAs and chromatin proteins play important roles in gene regulation, but the molecular details of most of these interactions are unknown. Using protein-RNA photocrosslinking and mass spectrometry on embryonic stem cell nuclei, we identified and mapped, at peptide resolution, the RNA-binding regions in ∼800 known and previously unknown RNA-binding proteins, many of which are transcriptional regulators and chromatin modifiers. In addition to known RNA-binding motifs, we detected several protein domains previously unknown to function in RNA recognition, as well as non-annotated and/or disordered regions, suggesting that many functional protein-RNA contacts remain unexplored...
October 20, 2016: Molecular Cell
David Olagnier, Cindy Chiang, John Hiscott
The dynamics of chromatin structure contribute to the regulation of gene transcription and in part, the changes in chromatin structure associated with gene activation/repression are a function of the state of histone acetylation. Histone deacetylases (HDACs) deacetylate histone tails leading to a more compact structure of chromatin that in turn represses gene transcription. Given the rapid activation and/or repression of gene networks following microbial infection, the role of HDACs in the epigenetic regulation of genes involved in the innate and adaptive immune responses has become an area of extensive research...
2017: Methods in Molecular Biology
Steven C L Ho, Esther Y C Koh, Benjamin P C Soo, Mariati, Sheng-Hao Chao, Yuansheng Yang
BACKGROUND: Methylated CpG dinucleotides in promoters are associated with the loss of gene expression in recombinant Chinese hamster ovary (CHO) cells during large-scale commercial manufacturing. We evaluated a promoter devoid of CpG dinucleotides, CpGfree, in parallel with a similar CpG containing promoter, CpGrich, for their ability to maintain the expression of recombinant enhanced green fluorescent protein (EGFP) after 8 weeks of culturing. RESULTS: While the promoters gave similar transient expression levels, CpGfree clones had significantly higher average stable expression possibly due to increased resistance to early silencing during integration into the chromosome...
October 18, 2016: BMC Biotechnology
H Chai, J Zhang, G Yang, Z Ma
DNA-binding proteins play a pivotal role in various biological activities. Identification of DNA-binding residues (DBRs) is of great importance for understanding the mechanism of gene regulations and chromatin remodeling. Most traditional computational methods usually construct their predictors on static non-redundant datasets. They excluded many homologous DNA-binding proteins so as to guarantee the generalization capability of their models. However, those ignored samples may potentially provide useful clues when studying protein-DNA interactions, which have not obtained enough attention...
October 12, 2016: Molecular BioSystems
Jonathan Hetzel, Sascha H Duttke, Christopher Benner, Joanne Chory
Transcriptional regulation of gene expression is a major mechanism used by plants to confer phenotypic plasticity, and yet compared with other eukaryotes or bacteria, little is known about the design principles. We generated an extensive catalog of nascent and steady-state transcripts in Arabidopsis thaliana seedlings using global nuclear run-on sequencing (GRO-seq), 5'GRO-seq, and RNA-seq and reanalyzed published maize data to capture characteristics of plant transcription. De novo annotation of nascent transcripts accurately mapped start sites and unstable transcripts...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Syed O Ali, Farhaan A Khan, Miguel A Galindo-Campos, José Yélamos
Poly(ADP-ribosyl)ation (PARylation) is a widespread and highly conserved post-translational modification catalysed by a large family of enzymes called poly(ADP-ribose) polymerases (PARPs). PARylation plays an essential role in various cardinal processes of cellular physiology and recent approvals and breakthrough therapy designations for PARP inhibitors in cancer therapy have sparked great interest in pharmacological targeting of PARP proteins. Although, many PARP inhibitors have been developed, existing compounds display promiscuous inhibition across the PARP superfamily which could lead to unwanted off-target effects...
2016: American Journal of Cancer Research
Guido Ferrari, Barton F Haynes, Scott Koenig, Jeffrey L Nordstrom, David M Margolis, Georgia D Tomaras
HIV-1 is a retrovirus that integrates into host chromatin and can remain transcriptionally quiescent in a pool of immune cells. This characteristic enables HIV-1 to evade both host immune responses and antiretroviral drugs, leading to persistent infection. Upon reactivation of proviral gene expression, HIV-1 envelope (HIV-1 Env) glycoproteins are expressed on the cell surface, transforming latently infected cells into targets for HIV-1 Env-specific monoclonal antibodies (mAbs), which can engage immune effector cells to kill productively infected CD4(+) T cells and thus limit the spread of progeny virus...
October 7, 2016: Nature Reviews. Drug Discovery
Qian Qin, Shenglin Mei, Qiu Wu, Hanfei Sun, Lewyn Li, Len Taing, Sujun Chen, Fugen Li, Tao Liu, Chongzhi Zang, Han Xu, Yiwen Chen, Clifford A Meyer, Yong Zhang, Myles Brown, Henry W Long, X Shirley Liu
BACKGROUND: Transcription factor binding, histone modification, and chromatin accessibility studies are important approaches to understanding the biology of gene regulation. ChIP-seq and DNase-seq have become the standard techniques for studying protein-DNA interactions and chromatin accessibility respectively, and comprehensive quality control (QC) and analysis tools are critical to extracting the most value from these assay types. Although many analysis and QC tools have been reported, few combine ChIP-seq and DNase-seq data analysis and quality control in a unified framework with a comprehensive and unbiased reference of data quality metrics...
October 3, 2016: BMC Bioinformatics
Anna-Karin Olsson, Jessica Cedervall
It has become increasingly clear that circulating immune cells in the body have a major impact on cancer development, progression, and outcome. The role of both platelets and neutrophils as independent regulators of various processes in cancer has been known for long, but it has quite recently emerged that the platelet-neutrophil interplay is yet a critical component to take into account during malignant disease. It was reported a few years ago that neutrophils in mice with cancer have increased propensity to form neutrophil extracellular traps (NETs) - web-like structures formed by externalized chromatin and secreted proteases...
2016: Frontiers in Immunology
Aditi Khandekar, Steven Springer, Wei Wang, Stephanie Hicks, Carla J Weinheimer, Ramon Diaz-Trelles, Jeanne M Nerbonne, Stacey Rentschler
RATIONALE: Ventricular arrhythmias often arise from the Purkinje-myocyte junction and are a leading cause of sudden cardiac death. Notch activation reprograms cardiac myocytes to an "induced Purkinje-like" state characterized by prolonged action potential duration and expression of Purkinje enriched genes. OBJECTIVE: To understand the mechanism by which canonical Notch signaling causes action potential prolongation. METHODS AND RESULTS: We find that endogenous Purkinje cells have reduced peak K(+) current, Ito and IK,slow when compared with ventricular myocytes...
October 3, 2016: Circulation Research
Yasser Riazalhosseini, Mark Lathrop
Genomics is revolutionizing our understanding of the molecular basis of renal cell carcinoma (RCC). The advent of unbiased genome-wide association studies has led to the discovery of previously unrecognized genetic predisposing factors that impact an individual's risk of developing RCC. Moreover, large-scale investigations of somatic alterations of the genomic and transcriptomic landscapes in tumours using next-generation sequencing technology have revealed new information on the molecular pathways that are characteristically disrupted in various RCC subtypes...
November 2016: Nature Reviews. Nephrology
Eric Lacazette
Chromatin immunoprecipitation followed by qPCR analysis (ChIP-qPCR) is a widely used technique to study gene expression. A large number of students in molecular biology and more generally in life sciences will be confronted with the use of this technique, which is quite difficult to set up and can lead to misinterpretation if not carefully managed. This article describes a four-session laboratory practical designed for Masters students to introduce this technique. During the practical, students work in pairs...
September 26, 2016: Biochemistry and Molecular Biology Education
Sara González, Alicia García, Enrique Vázquez, Rebeca Serrano, Mar Sánchez, Luis Quintales, Francisco Antequera
In the yeast genome, a large proportion of nucleosomes occupy well-defined and stable positions. While the contribution of chromatin remodelers and DNA binding proteins to maintain this organization is well established, the relevance of the DNA sequence to nucleosome positioning in the genome remains controversial. Through quantitative analysis of nucleosome positioning, we show that sequence changes distort the nucleosomal pattern at the level of individual nucleosomes in three species of Schizosaccharomyces and in Saccharomyces cerevisiae...
September 23, 2016: Genome Research
Max A Horlbeck, Luke A Gilbert, Jacqueline E Villalta, Britt Adamson, Ryan A Pak, Yuwen Chen, Alexander P Fields, Chong Y Park, Jacob E Corn, Martin Kampmann, Jonathan S Weissman
We recently found that nucleosomes directly block access of CRISPR/Cas9 to DNA (Horlbeck et al., 2016). Here, we build on this observation with a comprehensive algorithm that incorporates chromatin, position, and sequence features to accurately predict highly effective single guide RNAs (sgRNAs) for targeting nuclease-dead Cas9-mediated transcriptional repression (CRISPRi) and activation (CRISPRa). We use this algorithm to design next-generation genome-scale CRISPRi and CRISPRa libraries targeting human and mouse genomes...
September 23, 2016: ELife
Alec N Sexton, Martin Machyna, Matthew D Simon
There are numerous recent cases where chromatin modifying complexes associate with long noncoding RNA (lncRNA), stoking interest in lncRNA genomic localization and associated proteins. Capture Hybridization Analysis of RNA Targets (CHART) uses complementary oligonucleotides to purify an RNA with its associated genomic DNA or proteins from formaldehyde cross-linked chromatin. Deep sequencing of the purified DNA fragments gives a comprehensive profile of the potential lncRNA biological targets in vivo. The combined identification of the genomic localization of RNA and its protein partners can directly inform hypotheses about RNA function, including recruitment of chromatin modifying complexes...
2016: Methods in Molecular Biology
Miriam Gagliardi, Maria R Matarazzo
The relevance of RNA-protein interactions in modulating mRNA and noncoding RNA function is increasingly appreciated and several methods have been recently developed to map them. The RNA immunoprecipitation (RIP) is a powerful method to study the physical association between individual proteins and RNA molecules in vivo. The basic principles of RIP are very similar to those of chromatin immunoprecipitation (ChIP), a largely used tool in the epigenetic field, but with some important caveats. The approach is based on the use of a specific antibody raised against the protein of interest to pull down the RNA-binding protein (RBP) and target-RNA complexes...
2016: Methods in Molecular Biology
Apurva Jain, Lawrence N Kwong, Milind Javle
Biliary tract cancers are relatively uncommon, have an aggressive disease course and a dismal clinical outcome. Until recently, there have been very few clinical advances in the management of these patients and gemcitabine-based chemotherapy has been the only widely accepted systemic therapy. The advent of next generation sequencing technologies can potentially change the treatment paradigm of this disease. Targeted therapy directed against actionable mutations and identification of molecular subsets with distinct prognostic significance is now feasible in clinical practice...
November 2016: Current Treatment Options in Oncology
Xiaoqin Wang, Kaiyu Zhou, Yimin Hua, Yifei Li
INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is one of the most common cardiomyopathies, which induces sudden cardiac death. Several mutants have been identified among HCM cases. METHODS AND RESULTS: A 10-month female infant who experienced cough, fever, aggressive exertional dyspnea, and recurrent cyanosis was admitted to our hospital. The patient was first diagnosed with type I respiratory failure, dysfunction of heart, severe pneumonia, and also some cardiac disorders were suspected...
September 2016: Medicine (Baltimore)
Timothy Hardy, Derek A Mann
Knowledge of the fundamental epigenetic mechanisms governing gene expression and cellular phenotype are sufficiently advanced that novel insights into the epigenetic control of chronic liver disease are now emerging. Hepatologists are in the process of shedding light on the roles played by DNA methylation, histone/chromatin modifications and non-coding RNAs in specific liver pathologies. Alongside these discoveries are advances in the technologies for the detection and quantification of epigenetic biomarkers, either directly from patient tissue or from body fluids...
September 13, 2016: Gut
Vassilios Myrianthopoulos, Nicolas Gaboriaud-Kolar, Cynthia Tallant, Michelle-Lynn Hall, Stylianos Grigoriou, Peter Moore Brownlee, Oleg Fedorov, Catherine Rogers, David Heidenreich, Marek Wanior, Nikolaos Drosos, Nikitia Mexia, Pavel Savitsky, Tina Bagratuni, Efstathios Kastritis, Evangelos Terpos, Panagis Filippakopoulos, Susanne Müller, Alexios-Leandros Skaltsounis, Jessica Ann Downs, Stefan Knapp, Emmanuel Mikros
Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry...
October 13, 2016: Journal of Medicinal Chemistry
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