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Designer nucleosomes

David Remillard, Dennis L Buckley, Joshiawa Paulk, Gerard L Brien, Matthew Sonnett, Hyuk-Soo Seo, Shiva Dastierdi, Martin Wühr, Sirano Dhe-Paganon, Scott A Armstrong, James E Bradner
The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl-lysine recognition. We have therefore created the first BRD9-directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex...
April 18, 2017: Angewandte Chemie
Michal Levo, Tali Avnit-Sagi, Maya Lotan-Pompan, Yael Kalma, Adina Weinberger, Zohar Yakhini, Eran Segal
Precise gene expression patterns are established by transcription factor (TFs) binding to regulatory sequences. While these events occur in the context of chromatin, our understanding of how TF-nucleosome interplay affects gene expression is highly limited. Here, we present an assay for high-resolution measurements of both DNA occupancy and gene expression on large-scale libraries of systematically designed regulatory sequences. Our assay reveals occupancy patterns at the single-cell level. It provides an accurate quantification of the fraction of the population bound by a nucleosome and captures distinct, even adjacent, TF binding events...
February 16, 2017: Molecular Cell
Lingjie Liu, Jianming Xie, Xiao Sun, Kun Luo, Zhaohui Steve Qin, Hongde Liu
BACKGROUND: Nucleosome plays a role in transcriptional regulation through occluding the binding of proteins to DNA sites. Nucleosome occupancy varies among different cell types. Identification of such variation will help to understand regulation mechanism. The previous researches focused on the methods for two-sample comparison. However, a multiple-sample comparison (n ≥ 3) is necessary, especially in studying development and cancer. METHODS: Here, we proposed a Chi-squared test-based approach, named as Dimnp, to identify differential nucleosome regions (DNRs) in multiple samples...
February 7, 2017: BMC Genomics
Kimberly D Barnash, Juliana The, Jacqueline L Norris-Drouin, Stephanie H Cholensky, Beau M Worley, Fengling Li, Jacob I Stuckey, Peter J Brown, Masoud Vedadi, Cheryl H Arrowsmith, Stephen V Frye, Lindsey I James
The function of EED within polycomb repressive complex 2 (PRC2) is mediated by a complex network of protein-protein interactions. Allosteric activation of PRC2 by binding of methylated proteins to the embryonic ectoderm development (EED) aromatic cage is essential for full catalytic activity, but details of this regulation are not fully understood. EED's recognition of the product of PRC2 activity, histone H3 lysine 27 trimethylation (H3K27me3), stimulates PRC2 methyltransferase activity at adjacent nucleosomes leading to H3K27me3 propagation and, ultimately, gene repression...
March 13, 2017: ACS Combinatorial Science
A McNamara, J Perl, P Piersimoni, J Ramos-Mendez, B Faddegon, K Held, H Paganetti, J Schuemann
PURPOSE: New advances in radiation therapy are most likely to come from the complex interface of physics, chemistry and biology. Computational simulations offer a powerful tool for quantitatively investigating radiation interactions with biological tissue and can thus help bridge the gap between physics and biology. The aim of TOPAS-nBio is to provide a comprehensive tool to generate advanced radiobiology simulations. METHODS: TOPAS wraps and extends the Geant4 Monte Carlo (MC) simulation toolkit...
June 2016: Medical Physics
Sylvia A Hilliard, Samir S El-Dahr
An understanding of epigenetics is indispensable to our understanding of gene regulation under normal and pathological states. This knowledge will help with designing better therapeutic approaches in regenerative tissue medicine. Epigenetics allows us to parse out the mechanisms by which transcriptional regulators gain access to specific gene loci thereby imprinting epigenetic information affecting chromatin function. This epigenetic memory forms the basis of cell lineage specification in multicellular organisms...
December 2016: Yale Journal of Biology and Medicine
Rui M C Portela, Thomas Vogl, Claudia Kniely, Jasmin E Fischer, Rui Oliveira, Anton Glieder
Synthetic biology and metabolic engineering experiments frequently require the fine-tuning of gene expression to balance and optimize protein levels of regulators or metabolic enzymes. A key concept of synthetic biology is the development of modular parts that can be used in different contexts. Here, we have applied a computational multifactor design approach to generate de novo synthetic core promoters and 5' untranslated regions (UTRs) for yeast cells. In contrast to upstream cis-regulatory modules (CRMs), core promoters are typically not subject to specific regulation, making them ideal engineering targets for gene expression fine-tuning...
March 17, 2017: ACS Synthetic Biology
Lilien N Voong, Liqun Xi, Amy C Sebeson, Bin Xiong, Ji-Ping Wang, Xiaozhong Wang
Nucleosome organization influences gene activity by controlling DNA accessibility to transcription machinery. Here, we develop a chemical biology approach to determine mammalian nucleosome positions genome-wide. We uncovered surprising features of nucleosome organization in mouse embryonic stem cells. In contrast to the prevailing model, we observe that for nearly all mouse genes, a class of fragile nucleosomes occupies previously designated nucleosome-depleted regions around transcription start sites and transcription termination sites...
December 1, 2016: Cell
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...
November 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 This effect is equally detected in transcribed and nontranscribed regions, suggesting the existence of sequence elements that contribute to positioning...
November 2016: Genome Research
Max A Horlbeck, Luke A Gilbert, Jacqueline E Villalta, Britt Adamson, Ryan A Pak, Yuwen Chen, Alexander P Fields, Chong Yon 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...
December 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
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