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Designer chromatin

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https://www.readbyqxmd.com/read/28096241/the-chromodomain-helicase-dna-binding-chromatin-remodelers-family-traits-that-protect-from-and-promote-cancer
#1
Alea A Mills
A plethora of mutations in chromatin regulators in diverse human cancers is emerging, attesting to the pivotal role of chromatin dynamics in tumorigenesis. A recurrent theme is inactivation of the chromodomain helicase DNA-binding (CHD) family of proteins-ATP-dependent chromatin remodelers that govern the cellular machinery's access to DNA, thereby controlling fundamental processes, including transcription, proliferation, and DNA damage repair. This review highlights what is currently known about how genetic and epigenetic perturbation of CHD proteins and the pathways that they regulate set the stage for cancer, providing new insight for designing more effective anti-cancer therapies...
January 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28092380/chromatin-immunoprecipitation-in-microfluidic-droplets-towards-fast-and-cheap-analyses
#2
Bruno Teste, Jerome Champ, Arturo Londono-Vallejo, Stéphanie Descroix, Laurent Malaquin, Jean-Louis Viovy, Irena Draskovic, Guillaume Mottet
Genetic organization is governed by the interaction of DNA with histone proteins, and differential modifications of these proteins is a fundamental mechanism of gene regulation. Histone modifications are primarily studied through chromatin immunoprecipitation (ChIP) assays, however conventional ChIP procedures are time consuming, laborious and require a large number of cells. Here we report for the first time the development of ChIP in droplets based on a microfluidic platform combining nanoliter droplets, magnetic beads (MB) and magnetic tweezers (MT)...
January 16, 2017: Lab on a Chip
https://www.readbyqxmd.com/read/28090287/transcription-factors-transcriptional-coregulators-and-epigenetic-modulation-in-the-control-of-pulmonary-vascular-cell-phenotype-therapeutic-implications-for-pulmonary-hypertension-2015-grover-conference-series
#3
REVIEW
Soni S Pullamsetti, Frédéric Perros, Prakash Chelladurai, Jason Yuan, Kurt Stenmark
Pulmonary hypertension (PH) is a complex and multifactorial disease involving genetic, epigenetic, and environmental factors. Numerous stimuli and pathological conditions facilitate severe vascular remodeling in PH by activation of a complex cascade of signaling pathways involving vascular cell proliferation, differentiation, and inflammation. Multiple signaling cascades modulate the activity of certain sequence-specific DNA-binding transcription factors (TFs) and coregulators that are critical for the transcriptional regulation of gene expression that facilitates PH-associated vascular cell phenotypes, as demonstrated by several studies summarized in this review...
December 2016: Pulmonary Circulation
https://www.readbyqxmd.com/read/28089111/the-molecular-landscape-of-colitis-associated-carcinogenesis
#4
Deborah Saraggi, Matteo Fassan, Claudia Mescoli, Marco Scarpa, Nicola Valeri, Andrea Michielan, Renata D'Incá, Massimo Rugge
In spite of the well-established histopathological phenotyping of IBD-associated preneoplastic and neoplastic lesions, their molecular landscape remains to be fully elucidated. Several studies have pinpointed the initiating role of longstanding/relapsing inflammatory insult on the intestinal mucosa, with the activation of different pro-inflammatory cytokines (TNF-α, IL-6, IL-10, IFN-γ), chemokines and metabolites of arachidonic acid resulting in the activation of key transcription factors such as NF-κB. Longstanding inflammation may also modify the intestinal microbiota, prompting the overgrowth of genotoxic microorganisms, which may act as further cancer promoters...
December 21, 2016: Digestive and Liver Disease
https://www.readbyqxmd.com/read/28076866/biophysically-motivated-regulatory-network-inference-progress-and-prospects
#5
Tarmo Äijö, Richard Bonneau
Thanks to the confluence of genomic technology and computational developments, the possibility of network inference methods that automatically learn large comprehensive models of cellular regulation is closer than ever. This perspective focuses on enumerating the elements of computational strategies that, when coupled to appropriate experimental designs, can lead to accurate large-scale models of chromatin state and transcriptional regulatory structure and dynamics. We highlight 4 research questions that require further investigation in order to make progress in network inference: (1) using overall constraints on network structure such as sparsity, (2) use of informative priors and data integration to constrain individual model parameters, (3) estimation of latent regulatory factor activity under varying cell conditions, and (4) new methods for learning and modeling regulatory factor interactions...
2016: Human Heredity
https://www.readbyqxmd.com/read/28068427/s1-type-endonuclease-2-in-dedifferentiating-arabidopsis-protoplasts-translocation-to-the-nucleus-in-senescing-protoplasts-is-associated-with-de-glycosylation
#6
Yemima Givaty-Rapp, Narendra Singh Yadav, Asif Khan, Gideon Grafi
Cell dedifferentiation characterizes the transition of leaf cells to protoplasts and is accompanied by global chromatin decondensation. Here we show that in Arabidopsis, chromocentric chromatin undergoes prompt and gradual decondensation upon protoplasting. We hypothesized that prompt chromatin decondensation is unlikely to be driven solely by epigenetic means and other factors might be involved. We investigated the possibility that S1-type endonucleases are involved in prompt chromatin decondensation via their capability to target and cleave unpaired regions within superhelical DNA, leading to chromatin relaxation...
2017: PloS One
https://www.readbyqxmd.com/read/28068087/design-of-a-biased-potent-small-molecule-inhibitor-of-the-bromodomain-and-phd-finger-containing-brpf-proteins-suitable-for-cellular-and-in-vivo-studies
#7
Niall Igoe, Elliott D Bayle, Oleg Fedorov, Cynthia Tallant, Pavel Savitsky, Catherine Rogers, Dafydd R Owen, Gauri Deb, Tim C P Somervaille, David M Andrews, Neil Jones, Anne Cheasty, Hamish Ryder, Paul E Brennan, Susanne Müller, Stefan Knapp, Paul V Fish
The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines...
January 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28059770/a-supramolecular-assembly-mediates-lentiviral-dna-integration
#8
Allison Ballandras-Colas, Daniel P Maskell, Erik Serrao, Julia Locke, Paolo Swuec, Stefán R Jónsson, Abhay Kotecha, Nicola J Cook, Valerie E Pye, Ian A Taylor, Valgerdur Andrésdóttir, Alan N Engelman, Alessandro Costa, Peter Cherepanov
Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo-electron microscopy, we now visualize the functional maedi-visna lentivirus intasome at 4.9 angstrom resolution. The intasome comprises a homo-hexadecamer of IN with a tetramer-of-tetramers architecture featuring eight structurally distinct types of IN protomers supporting two catalytically competent subunits. The conserved intasomal core, previously observed in simpler retroviral systems, is formed between two IN tetramers, with a pair of C-terminal domains from flanking tetramers completing the synaptic interface...
January 6, 2017: Science
https://www.readbyqxmd.com/read/28056762/hic-bench-comprehensive-and-reproducible-hi-c-data-analysis-designed-for-parameter-exploration-and-benchmarking
#9
Charalampos Lazaris, Stephen Kelly, Panagiotis Ntziachristos, Iannis Aifantis, Aristotelis Tsirigos
BACKGROUND: Chromatin conformation capture techniques have evolved rapidly over the last few years and have provided new insights into genome organization at an unprecedented resolution. Analysis of Hi-C data is complex and computationally intensive involving multiple tasks and requiring robust quality assessment. This has led to the development of several tools and methods for processing Hi-C data. However, most of the existing tools do not cover all aspects of the analysis and only offer few quality assessment options...
January 5, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28050800/micro-rna-204-participates-in-tmprss2-erg-regulation-and-androgen-receptor-reprogramming-in-prostate-cancer
#10
Krassimira Todorova, Metodi V Metodiev, Gergana Metodieva, Milcho Mincheff, Nelson Fernández, Soren Hayrabedyan
Cancer progression is driven by genome instability incurred rearrangements such as transmembrane protease, serine 2 (TMPRSS2)/v-ets erythroblastosis virus E26 oncogene (ERG) that could possibly turn some of the tumor suppressor micro-RNAs into pro-oncogenic ones. Previously, we found dualistic miR-204 effects, acting either as a tumor suppressor or as an oncomiR in ERG fusion-dependent manner. Here, we provided further evidence for an important role of miR-204 for TMPRSS2/ERG and androgen receptor (AR) signaling modulation and fine tuning that prevents TMPRSS2/ERG overexpression in prostate cancer...
January 3, 2017: Hormones & Cancer
https://www.readbyqxmd.com/read/28048349/we-h-bra-04-biological-geometries-for-the-monte-carlo-simulation-toolkit-topasnbio
#11
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
https://www.readbyqxmd.com/read/28018145/epigenetics-of-renal-development-and-disease
#12
REVIEW
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
https://www.readbyqxmd.com/read/28002961/design-synthesis-and-biological-activity-of-substrate-competitive-smyd2-inhibitors
#13
Scott D Cowen, Daniel Russell, Leslie A Dakin, Huawei Chen, Nicholas A Larsen, Robert Godin, Scott Throner, Xiaolan Zheng, Audrey Molina, Jiaquan Wu, Tony Cheung, Tina Howard, Renee Garcia-Arenas, Nicholas Keen, Christopher S Pendleton, Jennifer A Pietenpol, Andrew D Ferguson
Protein lysine methyltransferases (KMTs) have emerged as important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from the cofactor S-adenosylmethionine to specific acceptor lysine residues on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate an array of nonhistone proteins, suggesting additional mechanisms by which they influence cellular physiology. SMYD2 is reported to be an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27992714/structure-guided-design-of-eed-binders-allosterically-inhibiting-the-epigenetic-polycomb-repressive-complex-2-prc2-methyltransferase
#14
Andreas Lingel, Martin Sendzik, Ying Huang, Michael D Shultz, John Cantwell, Michael P Dillon, Xingnian Fu, John Fuller, Tobias Gabriel, Justin Gu, Xiangqing Jiang, Ling Li, Fang Liang, Maureen McKenna, Wei Qi, Weijun Rao, Xijun Sheng, Wei Shu, James Sutton, Benjamin Taft, Long Wang, Jue Zeng, Hailong Zhang, Maya Zhang, Kehao Zhao, Mika Lindvall, Dirksen E Bussiere
PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit...
January 3, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27955897/orexins-mediate-sex-differences-in-the-stress-response-and-in-cognitive-flexibility
#15
Laura A Grafe, Amanda Cornfeld, Sandra Luz, Rita Valentino, Seema Bhatnagar
BACKGROUND: Women are twice as likely as men to experience stress-related psychiatric disorders. The biological basis of these sex differences is poorly understood. Orexins are altered in anxious and depressed patients. Using a rat model of repeated stress, we examined whether orexins contribute to sex differences in outcomes relevant to stress-related psychiatric diseases. METHODS: Behavioral, neural, and endocrine habituation to repeated restraint stress and subsequent cognitive flexibility was examined in adult male and female rats...
October 18, 2016: Biological Psychiatry
https://www.readbyqxmd.com/read/27941123/the-rna-induced-transcriptional-silencing-complex-targets-chromatin-exclusively-via-interacting-with-nascent-transcripts
#16
Yukiko Shimada, Fabio Mohn, Marc Bühler
Small RNAs regulate chromatin modification and transcriptional gene silencing across the eukaryotic kingdom. Although these processes have been well studied, fundamental mechanistic aspects remain obscure. Specifically, it is unclear exactly how small RNA-loaded Argonaute protein complexes target chromatin to mediate silencing. Here, using fission yeast, we demonstrate that transcription of the target locus is essential for RNA-directed formation of heterochromatin. However, high transcriptional activity is inhibitory; thus, a transcriptional window exists that is optimal for silencing...
December 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27927750/mdm2-as-a-chromatin-modifier
#17
REVIEW
Magdalena Wienken, Ute M Moll, Matthias Dobbelstein
Mdm2 is the key negative regulator of the tumour suppressor p53, making it an attractive target for anti-cancer drug design. We recently identified a new role of Mdm2 in gene repression through its direct interaction with several proteins of the polycomb group (PcG) family. PcG proteins form polycomb repressive complexes PRC1 and PRC2. PRC2 (via EZH2) mediates histone 3 lysine 27 (H3K27) trimethylation, and PRC1 (via RING1B) mediates histone 2A lysine 119 (H2AK119) monoubiquitination. Both PRCs mostly support a compact and transcriptionally silent chromatin structure...
November 9, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27923917/metadherin-astrocyte-elevated-gene-1-positively-regulates-the-stability-and-function-of-forkhead-box-m1-during-tumorigenesis
#18
Lixuan Yang, Kejun He, Sheng Yan, Yibing Yang, Xinya Gao, Maolei Zhang, Zhibo Xia, Zhengsong Huang, Suyun Huang, Nu Zhang
BACKGROUND: Forkhead box M1 (FOXM1) is overexpressed and activates numerous oncoproteins in tumors. However, the mechanism by which the FOXM1 protein aberrantly accumulates in human cancer remains uncertain. This study was designed to clarify the upstream signaling pathway(s) that regulate FOXM1 protein stability and transcriptional activity. METHODS: Mass spectrometry and immunoprecipitation were performed to identify the FOXM-metadherin (MTDH) interaction. In vivo and in vitro ubiquitination assays were conducted to test the effect of MTDH on FOXM1 stability...
December 6, 2016: Neuro-oncology
https://www.readbyqxmd.com/read/27923366/3c-digital-pcr-for-quantification-of-chromatin-interactions
#19
Meijun Du, Liang Wang
BACKGROUND: Chromosome conformation capture (3C) is a powerful and widely used technique for detecting the physical interactions between chromatin regions in vivo. The principle of 3C is to convert physical chromatin interactions into specific DNA ligation products, which are then detected by quantitative polymerase chain reaction (qPCR). However, 3C-qPCR assays are often complicated by the necessity of normalization controls to correct for amplification biases. In addition, qPCR is often limited to a certain cycle number, making it difficult to detect fragment ligations with low frequency...
December 6, 2016: BMC Molecular Biology
https://www.readbyqxmd.com/read/27906449/differential-mutation-frequencies-in-metastatic-cutaneous-squamous-cell-carcinomas-versus-primary-tumors
#20
Ayse Selen Yilmaz, Hatice Gulcin Ozer, Jessica L Gillespie, Dawn C Allain, Madison N Bernhardt, Karina Colossi Furlan, Leticia T F Castro, Sara B Peters, Priyadharsini Nagarajan, Stephen Y Kang, O Hans Iwenofu, Thomas Olencki, Theodoros N Teknos, Amanda Ewart Toland
BACKGROUND: Exome and targeted sequencing studies have identified potential driver mutations for a variety of tumor types. Cutaneous squamous cell carcinoma (cSCC) is one of the most highly mutated cancers but typically is associated with low rates of metastasis and high survival rates. Nevertheless, metastatic cSCC is a significant health threat; up to 8800 individuals die each year of this disease. METHODS: Because it is difficult to predict which cSCCs are more likely to metastasize, and because to the best of the authors' knowledge there are no targeted therapies specifically designated for patients with metastatic cSCC, exome and/or targeted sequencing of 18 metastatic and 10 primary cSCCs was performed to identify mutations that were more frequent in metastatic tumors and might be targeted for therapeutic benefit...
December 1, 2016: Cancer
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