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Designer chromatin

Nicolette Kapp, Xiao X Stander, Barend A Stander
This project investigated the in-vitro effects of a glycolytic inhibitor, 3-bromopyruvate (3-BrP), in combination with and a new in silico-designed inhibitor of the bromodomain-4 (BRD-4) protein, ITH-47, on the U937 acute myeloid leukemia cell line. 3-BrP is an agent that targets the altered metabolism of cancer cells by interfering with glucose metabolism in the glycolytic pathway. ITH-47 is an acetyl-lysine inhibitor that displaces bromdomain 4 proteins from chromatin by competitively binding to the acetyl-lysine recognition pocket of this bromodomain and extraterminal (BET) BRD protein, thereby preventing transcription of cancer-associated genes and further cell growth...
March 20, 2018: Anti-cancer Drugs
Matteo Lo Monte, Candida Manelfi, Marica Gemei, Daniela Corda, Andrea Rosario Beccari
Motivation: ADP-ribosylation is a post-translational modification implicated in several crucial cellular processes, ranging from regulation of DNA repair and chromatin structure to cell metabolism and stress responses. To date, a complete understanding of ADP-ribosylation targets and their modification sites in different tissues and disease states is still lacking. Identification of ADP-ribosylation sites is required to discern the molecular mechanisms regulated by this modification. This motivated us to develop a computational tool for the prediction of ADP-ribosylated sites...
March 15, 2018: Bioinformatics
Jin-Chun Lu, Jun Jing, Li Chen, Yi-Feng Ge, Rui-Xiang Feng, Yuan-Jiao Liang, Bing Yao
BACKGROUND: Many factors may lead to sperm DNA damage. However, it is little known that the correlations of sperm DNA damage with obesity-associated markers, and reproductive hormones and lipids levels in serum and seminal plasma. METHODS: In our prospective study, a total of 1 010 subfertile men, aged from 18 to 50 years old, were enrolled from August 2012 through June 2015. Their obesity-associated markers, semen parameters, sperm acrosomal enzyme activity, seminal plasma biochemical markers, and reproductive hormones and lipids levels in serum and seminal plasma were detected...
March 14, 2018: Reproductive Biology and Endocrinology: RB&E
Tafadzwa Mlambo, Sandra Nitsch, Markus Hildenbeutel, Marianna Romito, Maximilian Müller, Claudia Bossen, Sven Diederichs, Tatjana I Cornu, Toni Cathomen, Claudio Mussolino
Targeted modulation of gene expression represents a valuable approach to understand the mechanisms governing gene regulation. In a therapeutic context, it can be exploited to selectively modify the aberrant expression of a disease-causing gene or to provide the target cells with a new function. Here, we have established a novel platform for achieving precision epigenome editing using designer epigenome modifiers (DEMs). DEMs combine in a single molecule a DNA binding domain based on highly specific transcription activator-like effectors (TALEs) and several effector domains capable of inducing DNA methylation and locally altering the chromatin structure to silence target gene expression...
March 10, 2018: Nucleic Acids Research
Kelly A Campen, Katherine M Kucharczyk, Benjamin Bogin, Julie M Ehrlich, Catherine M H Combelles
STUDY QUESTION: What are the effects of exposure to bisphenol A (BPA) or bisphenol S (BPS) during IVM on bovine oocyte maturation, spindle morphology and chromosome alignment? SUMMARY ANSWER: Exposure to BPA or BPS during IVM resulted in increased spindle abnormalities and chromosome misalignment, even at very low concentrations. WHAT IS KNOWN ALREADY: BPA is an endocrine disrupting chemical that alters oocyte maturation, spindle morphology and chromosome alignment in a range of species...
March 12, 2018: Human Reproduction
Patricia Santofimia-Castaño, Bruno Rizzuti, Olga Abián, Adrián Velázquez-Campoy, Juan L Iovanna, José L Neira
BACKGROUND: NUPR1 is a multifunctional intrinsically disordered protein (IDP) involved, among other functions, in chromatin remodelling, and development of pancreatic ductal adenocarcinoma (PDAC). It interacts with several biomolecules through hydrophobic patches around residues Ala33 and Thr68. The drug trifluoperazine (TFP), which hampers PDAC development in xenografted mice, also binds to those regions. Because of the large size of the hot-spot interface of NUPR1, small molecules could not be adequate to modulate its functions...
March 9, 2018: Biochimica et Biophysica Acta
Georgi K Marinov, Anshul Kundaje
Advances in the methods for detecting protein-DNA interactions have played a key role in determining the directions of research into the mechanisms of transcriptional regulation. The most recent major technological transformation happened a decade ago, with the move from using tiling arrays [chromatin immunoprecipitation (ChIP)-on-Chip] to high-throughput sequencing (ChIP-seq) as a readout for ChIP assays. In addition to the numerous other ways in which it is superior to arrays, by eliminating the need to design and manufacture them, sequencing also opened the door to carrying out comparative analyses of genome-wide transcription factor occupancy across species and studying chromatin biology in previously less accessible model and nonmodel organisms, thus allowing us to understand the evolution and diversity of regulatory mechanisms in unprecedented detail...
February 26, 2018: Briefings in Functional Genomics
Yohei Mikami, Gianluca Scarno, Beatrice Zitti, Han-Yu Shih, Yuka Kanno, Angela Santoni, John J O'Shea, Giuseppe Sciumè
Innate lymphoid cells (ILCs) producing IL-22 and/or IL-17, designated as ILC3, comprise a heterogeneous subset of cells involved in regulation of gut barrier homeostasis and inflammation. Exogenous environmental cues in conjunction with regulated expression of endogenous factors are key determinants of plasticity of ILC3 towards the type 1 fate. Herein, by using mouse models and transcriptomic approaches, we defined at the molecular level, initial events driving ILC3 expressing natural cytotoxicity receptors (NCR+ ILC3) to acquire type 1 features...
March 9, 2018: European Journal of Immunology
Désirée Goubert, Mihály Koncz, Antal Kiss, Marianne G Rots
Epigenetic editing is a promising approach to modulate the local chromatin environment of target genes with the ultimate goal of stable gene expression reprogramming. Epigenetic editing tools minimally consist of a DNA-binding domain and an effector domain. The CRISPR/dCas9 platform, where mutations in the nuclease domains render the Cas9 protein inactive, is widely used to guide epigenetic effectors to their intended genomic loci. Its flexible nature, simple use, and relatively low cost have revolutionized the research field of epigenetic editing...
2018: Methods in Molecular Biology
Carolin Kroll, Philipp Rathert
The advent of precise genomic targeting systems has revolutionized epigenome editing through fusion of epigenetic effector proteins with engineered DNA-binding proteins. However, the delivery of plasmid DNA to express these fusion proteins via conventional transient transfection has certain consequences which need to be considered during the experimental design. Transient transfection achieves peak gene expression between 24 and 96 h post-transfection after which the foreign gene is lost through cell division and degradation...
2018: Methods in Molecular Biology
Pavel Bashtrykov, Albert Jeltsch
The discovery and adaptation of the CRISPR/Cas system for epigenome editing has allowed for a straightforward design of targeting modules which can direct epigenetic editors to virtually any genomic site. This advancement in DNA-targeting technology brings allele-specific epigenome editing into reach, a "super-specific" variation of epigenome editing whose goal is an alteration of chromatin marks at only one selected allele of the target genomic locus. This technology would be useful for the treatment of diseases caused by a mutant allele with a dominant effect, because allele-specific epigenome editing allows the specific silencing of the mutated allele leaving the healthy counterpart expressed...
2018: Methods in Molecular Biology
Dilara Sen, Albert J Keung
The advent of locus-specific protein recruitment technologies has enabled a new class of studies in chromatin biology. Epigenome editors enable biochemical modifications of chromatin at almost any specific endogenous locus. Their locus specificity unlocks unique information including the functional roles of distinct modifications at specific genomic loci. Given the growing interest in using these tools for biological and translational studies, there are many specific design considerations depending on the scientific question or clinical need...
2018: Methods in Molecular Biology
Charlene Babra Waryah, Colette Moses, Mahira Arooj, Pilar Blancafort
The completion of genome, epigenome, and transcriptome mapping in multiple cell types has created a demand for precision biomolecular tools that allow researchers to functionally manipulate DNA, reconfigure chromatin structure, and ultimately reshape gene expression patterns. Epigenetic editing tools provide the ability to interrogate the relationship between epigenetic modifications and gene expression. Importantly, this information can be exploited to reprogram cell fate for both basic research and therapeutic applications...
2018: Methods in Molecular Biology
Chiara Antoniani, Vasco Meneghini, Annalisa Lattanzi, Tristan Felix, Oriana Romano, Elisa Magrin, Leslie Weber, Giulia Pavani, Sara El Hoss, Ryo Kurita, Yukio Nakamura, Thomas J Cradick, Ante S Lundberg, Matthew Porteus, Mario Amendola, Wassim El Nemer, Marina Cavazzana, Fulvio Mavilio, Annarita Miccio
Naturally occurring, large deletions in the β-globin locus result in hereditary persistence of fetal hemoglobin, a condition that mitigates the clinical severity of sickle-cell disease (SCD) and β-thalassemia. We designed a CRISPR/Cas9 strategy to disrupt a 13.6-kb genomic region encompassing the δ- and β-globin genes and a putative γ-δ intergenic fetal hemoglobin (HbF) silencer. Disruption of just the putative HbF silencer results in a mild increase in γ-globin expression, whereas deletion or inversion of a 13...
March 8, 2018: Blood
Yusuke Sakai, Makiko Koike, Daisuke Kawahara, Hideko Hasegawa, Tomomi Murai, Kosho Yamanouchi, Akihiko Soyama, Masaaki Hidaka, Mitsuhisa Takatsuki, Fumihiko Fujita, Tamotsu Kuroki, Susumu Eguchi
Engineered primary hepatocytes, including co-cultured hepatocyte sheets, are an attractive to basic scientific and clinical researchers because they maintain liver-specific functions, have reconstructed cell polarity, and have high transplantation efficiency. However, co-culture conditions regarding engineered primary hepatocytes were suboptimal in promoting these advantages. Here we report that the hepatocyte morphology and liver-specific function levels are controlled by the normal human diploid fibroblast (TIG-118 cell) layer cell density...
March 5, 2018: Journal of Bioscience and Bioengineering
Mitsuaki Yamashita, Teruyuki Tahara, Shinya Hayakawa, Hironobu Matsumoto, Shun-Ichi Wada, Kiyoshi Tomioka, Akira Iida
HDAC inhibitors enable histones to maintain a high degree of acetylation. The resulting looser state of chromatin DNA may increase the accessibility of DNA drug targets and consequently improve the efficiency of anticancer drugs targeting DNA, such as Topo II inhibitors. A novel class of nucleoside-SAHA derivatives has been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities toward histone deacetylases and Topo II, and their cytotoxicities in cancer cell lines, were evaluated...
February 27, 2018: Bioorganic & Medicinal Chemistry
Zenab F Mchaourab, Andrea A Perreault, Bryan J Venters
The human K562 chronic myeloid leukemia cell line has long served as an experimental paradigm for functional genomic studies. To systematically and functionally annotate the human genome, the ENCODE consortium generated hundreds of functional genomic data sets, such as chromatin immunoprecipitation coupled to sequencing (ChIP-seq). While ChIP-seq analyses have provided tremendous insights into gene regulation, spatiotemporal insights were limited by a resolution of several hundred base pairs. ChIP-exonuclease (ChIP-exo) is a refined version of ChIP-seq that overcomes this limitation by providing higher precision mapping of protein-DNA interactions...
March 6, 2018: Scientific Data
Silvia Kocanova, Isabelle Goiffon, Kerstin Bystricky
Fluorescence in situ hybridization (FISH) is a common technique used to label DNA and/or RNA for detection of a genomic region of interest. However, the technique can be challenging, in particular when applied to single genes in human cancer cells. Here, we provide a step-by-step protocol for analysis of short (35kb to 300kb) genomic regions in three dimensions (3D). We discuss the experimental design and provide practical considerations for 3D imaging and data analysis to determine chromatin folding. We demonstrate that 3D FISH using BACs (Bacterial Artificial Chromosomes) or fosmids can provide detailed information of the architecture of gene domains...
February 28, 2018: Methods: a Companion to Methods in Enzymology
Simon Nadal, Ritu Raj, Shabaz Mohammed, Benjamin G Davis
Chromatin is the physiological template of genetic information in all eukaryotic cells, a highly organised complex of DNA and histone proteins central in regulating gene expression and genome organisation. A multitude of histone post-translational modifications (PTMs) have been discovered, providing a glance into the complex interplay of these epigenetic marks in cellular processes. In the last decade, synthetic and chemical biology techniques have emerged to study these modifications, including genetic code expansion, histone semisynthesis and post-translational chemical mutagenesis...
February 28, 2018: Current Opinion in Chemical Biology
Manuela Lanzafame, Gaia Bianco, Luigi M Terracciano, Charlotte K Y Ng, Salvatore Piscuoglio
Whole-transcriptome analyses have revealed that a large proportion of the human genome is transcribed in non-protein-coding transcripts, designated as long non-coding RNAs (lncRNAs). Rather than being "transcriptional noise", increasing evidence indicates that lncRNAs are key players in the regulation of many biological processes, including transcription, post-translational modification and inhibition and chromatin remodeling. Indeed, lncRNAs are widely dysregulated in human cancers, including hepatocellular carcinoma (HCC)...
February 28, 2018: International Journal of Molecular Sciences
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