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Designer nucleosomes

Michael Tsabar, Wade M Hicks, Olga Tsaponina, James E Haber
Homologous recombination (HR) is an evolutionarily conserved pathway in eukaryotes that repairs a double-strand break (DSB) by copying homologous sequences from a sister chromatid, a homologous chromosome or an ectopic location. Recombination is challenged by the packaging of DNA into nucleosomes, which may impair the process at many steps, from resection of the DSB ends to the re-establishement of nucleosomes after repair. However, nucleosome dynamics during DSB repair have not been well described, primarily because of a lack of well-ordered nucleosomes around a DSB...
September 28, 2016: DNA Repair
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
Chiara Marabelli, Biagina Marrocco, Andrea Mattevi
LSD1 was the first discovered histone demethylase. Using a flavin-dependent oxidative mechanism, LSD1 demethylates the N-terminal tail of histone H3 in the context of a variety of developmental processes. This functional complexity involves the association with nuclear factors and non-coding RNAs. A number of exciting studies are uncovering the bases of these specific and diverse molecular interactions, which occur both at catalytic and non-catalytic regions of the enzyme. Alternative splicing and post-translation modifications represent further layers for modulating this complex molecular network...
July 25, 2016: Current Opinion in Structural Biology
Nang T T Htike, Fumihiko Maekawa, Haruka Soutome, Kazuhiro Sano, Sho Maejima, Kyaw H Aung, Masaaki Tokuda, Shinji Tsukahara
There is serious concern about arsenic in the natural environment, which exhibits neurotoxicity and increases the risk of neurodevelopmental disorders. Adverse effects of arsenic have been demonstrated in neurons, but it is not fully understood how arsenic affects other cell types in the brain. In the current study, we examined whether sodium arsenite (NaAsO2) affects the cell cycle, viability, and apoptosis of in vitro-cultured astrocytes isolated from the cerebral cortex of mice. Cultured astrocytes from transgenic mice expressing fluorescent ubiquitination-based cell cycle indicator (Fucci) were subjected to live imaging analysis to assess the effects of NaAsO2 (0, 1, 2, and 4 μM) on the cell cycle and number of cells...
2016: Frontiers in Neuroscience
Jenny V Le, Yi Luo, Michael A Darcy, Christopher R Lucas, Michelle F Goodwin, Michael G Poirier, Carlos E Castro
The organization of eukaryotic DNA into nucleosomes and chromatin undergoes dynamic structural changes to regulate genome processing, including transcription and DNA repair. Critical chromatin rearrangements occur over a wide range of distances, including the mesoscopic length scale of tens of nanometers. However, there is a lack of methodologies that probe changes over this mesoscopic length scale within chromatin. We have designed, constructed, and implemented a DNA-based nanocaliper that probes this mesoscopic length scale...
July 26, 2016: ACS Nano
Robert A McKnight, Christian C Yost, Erin K Zinkhan, Qi Fu, Christopher W Callaway, Camille M Fung
Nutrient deprivation suppresses protein synthesis by blocking peptide elongation. Transcriptional upregulation and activation of eukaryotic elongation factor 2 kinase (eEF2K) blocks peptide elongation by phosphorylating eukaryotic elongation factor 2. Previous studies examining placentas from intrauterine growth restricted (IUGR) newborn infants show decreased eEF2K expression and activity despite chronic nutrient deprivation. However, the effect of IUGR on hepatic eEF2K expression in the fetus is unknown. We, therefore, examined the transcriptional regulation of hepatic eEF2K gene expression in a Sprague-Dawley rat model of IUGR...
August 1, 2016: Physiological Genomics
Louise Rasmussen, Marielle Herzog, Eva Rømer, Jake Micallef, Orhan Bulut, Michael Wilhelmsen, Ib Jarle Christensen, Hans J Nielsen
AIM: To evaluate pre-analytical variables of circulating cell-free nucleosomes containing 5-methylcytosine DNA (5mC) or histone modification H3K9Me3 (H3K9Me3). MATERIALS AND METHODS: Six studies were designed to assess the possible influence of pre-analytical variables. Study 1: influence of stasis and contamination with white-cells and platelets. Study 2: influence of within-day variations. Study 3: influence of day-to-day variation. Study 4: influence of temperature during handling and storage, and of neoplastic disease...
October 2016: Scandinavian Journal of Clinical and Laboratory Investigation
Simone Sidoli, Natarajan V Bhanu, Kelly R Karch, Xiaoshi Wang, Benjamin A Garcia
Nucleosomes are the smallest structural unit of chromatin, composed of 147 base pairs of DNA wrapped around an octamer of histone proteins. Histone function is mediated by extensive post-translational modification by a myriad of nuclear proteins. These modifications are critical for nuclear integrity as they regulate chromatin structure and recruit enzymes involved in gene regulation, DNA repair and chromosome condensation. Even though a large part of the scientific community adopts antibody-based techniques to characterize histone PTM abundance, these approaches are low throughput and biased against hypermodified proteins, as the epitope might be obstructed by nearby modifications...
2016: Journal of Visualized Experiments: JoVE
Muhammad Tahir, Maqsood Hayat
The nucleosome is the fundamental unit of eukaryotic chromatin, which participates in regulating different cellular processes. Owing to the huge exploration of new DNA primary sequences, it is indispensable to develop an automated model. However, identification of novel protein sequences using conventional methods is difficult or sometimes impossible because of vague motifs and the intricate structure of DNA. In this regard, an effective and high throughput automated model "iNuc-STNC" has been proposed in order to identify accurately and reliably nucleosome positioning in genomes...
July 19, 2016: Molecular BioSystems
Rithy Meas, Michael J Smerdon
Base excision repair (BER) processes non-helix distorting lesions (e.g., uracils and gaps) and is composed of two subpathways that differ in the number of nucleotides (nts) incorporated during the DNA synthesis step: short patch (SP) repair incorporates 1 nt and long patch (LP) repair incorporates 2-12 nts. This choice for either LP or SP repair has not been analyzed in the context of nucleosomes. Initial studies with uracil located in nucleosome core DNA showed a distinct DNA polymerase extension profile in cell-free extracts that specifically limits extension to 1 nt, suggesting a preference for SP BER...
2016: Scientific Reports
Gavin D Bascom, Karissa Y Sanbonmatsu, Tamar Schlick
While it is well-recognized that chromatin loops play an important role in gene regulation, structural details regarding higher order chromatin loops are only emerging. Here we present a systematic study of restrained chromatin loops ranging from 25 to 427 nucleosomes (fibers of 5-80 Kb DNA in length), mimicking gene elements studied by 3C contact data. We find that hierarchical looping represents a stable configuration that can effectively bring distant regions of the GATA-4 gene together, satisfying connections reported by 3C experiments...
August 25, 2016: Journal of Physical Chemistry. B
Chun-Nan Dong, Ya-Dong Yang, Shu-Jin Li, Ya-Ran Yang, Xiao-Jing Zhang, Xiang-Dong Fang, Jiang-Wei Yan, Bin Cong
In the case of mass disasters, missing persons and forensic caseworks, highly degraded biological samples are often encountered. It can be a challenge to analyze and interpret the DNA profiles from these samples. Here we provide a new strategy to solve the problem by taking advantage of the intrinsic structural properties of DNA. We have assessed the in vivo positions of more than 35 million putative nucleosome cores in human leukocytes using high-throughput whole genome sequencing, and identified 2,462 single nucleotide variations (SNVs), 128 insertion-deletion polymorphisms (indels)...
2016: Scientific Reports
Liguo Geng, Meng Zhu, Yuzhuo Wang, Yang Cheng, Jia Liu, Wei Shen, Zhihua Li, Jiahui Zhang, Cheng Wang, Guangfu Jin, Hongxia Ma, Hongbing Shen, Zhibin Hu, Juncheng Dai
Chromatin remodeling complexes utilize the energy of ATP hydrolysis to remodel nucleosomes and have essential roles in transcriptional modulation. Increasing evidences indicate that these complexes directly interact with numerous proteins and regulate the formation of cancer. However, few studies reported the association of polymorphisms in chromatin remodeling genes and lung cancer. We hypothesized that variants in critical genes of chromatin remodeling pathway might contribute to the susceptibility of lung cancer...
August 10, 2016: Gene
Romain Fenouil, Nicolas Descostes, Lionel Spinelli, Frederic Koch, Muhammad Ahmad Maqbool, Touati Benoukraf, Pierre Cauchy, Charlène Innocenti, Pierre Ferrier, Jean-Christophe Andrau
UNLABELLED: We describe an R package designed for processing aligned reads from chromatin-oriented high-throughput sequencing experiments. Pasha (preprocessing of aligned sequences from HTS analyses) allows easy manipulation of aligned reads from short-read sequencing technologies (ChIP-seq, FAIRE-seq, MNase-Seq, …) and offers innovative approaches such as ChIP-seq reads elongation, nucleosome midpoint piling strategy for positioning analyses, or the ability to subset paired-end reads by groups of insert size that can contain biologically relevant information...
August 15, 2016: Bioinformatics
Tingting Zou, Seiichiro Kizaki, Ganesh N Pandian, Hiroshi Sugiyama
To evaluate the reactivity of antitumor agents in a nucleosome architecture, we conducted in vitro studies to assess the alkylation level of duocarmycin B2 on nucleosomes with core and linker DNA using sequencing gel electrophoresis. Our results suggested that the alkylating efficiencies of duocarmycin B2 were significantly decreased in core DNA and increased at the histone-free linker DNA sites when compared with naked DNA conditions. Our finding that nucleosome assembly alters the accessibility of duocarmycin B2 to duplex DNA could advance its design as an antitumor agent...
June 20, 2016: Chemistry: a European Journal
Justin D Smith, Sundari Suresh, Ulrich Schlecht, Manhong Wu, Omar Wagih, Gary Peltz, Ronald W Davis, Lars M Steinmetz, Leopold Parts, Robert P St Onge
BACKGROUND: Genome-scale CRISPR interference (CRISPRi) has been used in human cell lines; however, the features of effective guide RNAs (gRNAs) in different organisms have not been well characterized. Here, we define rules that determine gRNA effectiveness for transcriptional repression in Saccharomyces cerevisiae. RESULTS: We create an inducible single plasmid CRISPRi system for gene repression in yeast, and use it to analyze fitness effects of gRNAs under 18 small molecule treatments...
2016: Genome Biology
Wanessa F Cabral, Angelo H L Machado, Guilherme M Santos
Constant changes in the structure of chromatin regulate gene expression. Molecules that bind to the nucleosome, the complex of DNA and histone proteins, are key modulators of chromatin structure. Conceptually, the nucleosome was first identified as a therapeutic target 14 years ago, when small molecules started to be elegantly designed for nucleosomal DNA binding. Concomitantly, emergent drugs that target enzymes that affect chromatin structure have been developed to a treat myriad of diseases, such as cancer...
May 2016: Drug Discovery Today
Linjiao Zhou, Matthew T Holt, Nami Ohashi, Aishan Zhao, Manuel M Müller, Boyuan Wang, Tom W Muir
Ubiquitylation of histone H2B at lysine 120 (H2B-Ub), a post-translational modification first discovered in 1980, plays a critical role in diverse nuclear processes including the regulation of transcription and DNA damage repair. Herein, we use a suite of protein chemistry methods to explore how H2B-Ub stimulates hDot1L-mediated methylation of histone H3 on lysine 79 (H3K79me). By using semisynthetic 'designer' chromatin containing H2B-Ub bearing a site-specifically installed photocrosslinker, here we report an interaction between a functional hotspot on ubiquitin and the N-terminus of histone H2A...
2016: Nature Communications
Willie W Hsu, Bo Wu, Wenshe R Liu
Lysine acetylation serves as an epigenetic marker for myriad cellular processes, such as signaling, differentiation, DNA repair, angiogenesis, and the like. Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD(+)-dependent histone deacetylases that operate as post-translational regulators for the deacetylation of acetyllysine. Here, we discuss the ability for SIRT1 and SIRT2 to deacetylate monoacetylated histone H3 on two separate architectures-the peptide and the nucleosome. In addition, we analyze the site-specificity of SIRT1 and SIRT2 on 10 different monoacetylated histone H3 nucleosomes...
March 18, 2016: ACS Chemical Biology
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