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Chromatin modulation

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https://www.readbyqxmd.com/read/29684672/epigenetic-modulation-by-small-molecule-compounds-for-neurodegenerative-disorders
#1
REVIEW
Akash Kumar Singh, Sarmistha Halder Sinha, James P Clement, Tapas K Kundu
The accumulation of somatic and genetic mutations which altered the structure and coding information of the DNA are the major cause of neurological disorders. However, our recent understanding of molecular mechanisms of 'epigenetic' phenomenon reveals that the modifications of chromatin play a significant role in the development and severity of neurological disorders. These epigenetic processes are dynamic and reversible as compared to genetic ablations which are stable and irreversible. Therefore, targeting these epigenetic processes through small molecule modulators are of great therapeutic potential...
April 20, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29684361/high-frequency-of-ovarian-cyst-development-in-vhl-2b-snf5-mice
#2
Yasumichi Kuwahara, Leslie M Kennedy, Anthony N Karnezis, E Lorena Mora-Blanco, Arlin B Rogers, Christopher D Fletcher, David G Huntsman, Charles W M Roberts, W Kimryn Rathmell, Bernard E Weissman
The new paradigm of mutations in chromatin modifying genes as driver events in the development of cancers has proved challenging to resolve the complex influences over disease phenotypes. In particular, impaired activities of members of the SWI/SNF chromatin remodeling complex have appeared in an increasing variety of tumors. Mutations in SNF5, a member of this ubiquitously expressed complex, arise in almost all cases of malignant rhabdoid tumor in the absence of additional genetic alterations. Therefore, we studied how activation of additional oncogenic pathways might shift the phenotype of disease driven by SNF5 loss...
April 20, 2018: American Journal of Pathology
https://www.readbyqxmd.com/read/29684168/emerin-modulates-spatial-organization-of-chromosome-territories-in-cells-on-softer-matrices
#3
Roopali Pradhan, Devika Ranade, Kundan Sengupta
Cells perceive and relay external mechanical forces into the nucleus through the nuclear envelope. Here we examined the effect of lowering substrate stiffness as a paradigm to address the impact of altered mechanical forces on nuclear structure-function relationships. RNA sequencing of cells on softer matrices revealed significant transcriptional imbalances, predominantly in chromatin associated processes and transcriptional deregulation of human Chromosome 1. Furthermore, 3-Dimensional fluorescence in situ hybridization (3D-FISH) analyses showed a significant mislocalization of Chromosome 1 and 19 Territories (CT) into the nuclear interior, consistent with their transcriptional deregulation...
April 19, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29683440/an-integrated-platform-for-genome-wide-mapping-of-chromatin-states-using-high-throughput-chip-sequencing-in-tumor-tissues
#4
Christopher Terranova, Ming Tang, Elias Orouji, Mayinuer Maitituoheti, Ayush Raman, Samirkumar Amin, Zhiyi Liu, Kunal Rai
Histone modifications constitute a major component of the epigenome and play important regulatory roles in determining the transcriptional status of associated loci. In addition, the presence of specific modifications has been used to determine the position and identity non-coding functional elements such as enhancers. In recent years, chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) has become a powerful tool in determining the genome-wide profiles of individual histone modifications...
April 5, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29682190/the-jmjn-domain-as-a-dimerization-interface-and-a-targeted-inhibitor-of-kdm4-demethylase-activity
#5
May Levin, Michal Stark, Yehuda G Assaraf
Histone methylation is regulated to shape the epigenome by modulating DNA compaction, thus playing central roles in fundamental chromatin-based processes including transcriptional regulation, DNA repair and cell proliferation. Histone methylation is erased by demethylases including the well-established KDM4 subfamily members, however, little is known about their dimerization capacity and its impact on their demethylase activity. Using the powerful bimolecular fluorescence complementation technique, we herein show the in situ formation of human KDM4A and KDM4C homodimers and heterodimers in nuclei of live transfectant cells and evaluate their H3K9me3 demethylation activity...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29682174/esophageal-squamous-cell-carcinoma-transcriptome-reveals-the-effect-of-foxm1-on-patient-outcome-through-novel-pik3r3-mediated-activation-of-pi3k-signaling-pathway
#6
Pedro Nicolau-Neto, Nathalia Meireles Da Costa, Paulo Thiago de Souza Santos, Isabela Martins Gonzaga, Maria Aparecida Ferreira, Simone Guaraldi, Miguel Angelo Moreira, Hector N Seuánez, Lilian Brewer, Anke Bergmann, Mariana Boroni, Andre Luiz Mencalha, Cleber Dario Pinto Kruel, Sheila Coelho Soares Lima, Dominic Esposito, Tatiana Almeida Simão, Luis Felipe Ribeiro Pinto
Esophageal squamous cell carcinoma (ESCC) presents poor prognosis, and patients diagnosed with this tumor currently lack target treatments. Therefore, in order to identify potential targets for ESCC treatment, we carried out a transcriptome analysis with ESCC and paired nonmalignant surrounding mucosa samples, followed by a master regulator analysis, and further explored the role of the identified central regulatory genes through in vivo and in vitro assays. Among the transcription factors deregulated/enriched in ESCC, we focused on FOXM1 because of its involvement in the regulation of critical biological processes...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29681498/distinct-stimulatory-mechanisms-regulate-the-catalytic-activity-of-polycomb-repressive-complex-2
#7
Chul-Hwan Lee, Marlene Holder, Daniel Grau, Ricardo Saldaña-Meyer, Jia-Ray Yu, Rais Ahmad Ganai, Jenny Zhang, Miao Wang, Gary LeRoy, Marc-Werner Dobenecker, Danny Reinberg, Karim-Jean Armache
The maintenance of gene expression patterns during metazoan development is achieved, in part, by the actions of polycomb repressive complex 2 (PRC2). PRC2 catalyzes mono-, di-, and trimethylation of histone H3 at lysine 27 (H3K27), with H3K27me2/3 being strongly associated with silenced genes. We demonstrate that EZH1 and EZH2, the two mutually exclusive catalytic subunits of PRC2, are differentially activated by various mechanisms. Whereas both PRC2-EZH1 and PRC2-EZH2 are able to catalyze mono- and dimethylation, only PRC2-EZH2 is strongly activated by allosteric modulators and specific chromatin substrates to catalyze trimethylation of H3K27 in mouse embryonic stem cells (mESCs)...
April 13, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29678609/fat-nucleosome-role-of-lipids-on-chromatin
#8
REVIEW
Vinicius Fernandes, Kaian Teles, Camyla Ribeiro, Werner Treptow, Guilherme Santos
Structural changes in chromatin regulate gene expression and define phenotypic outcomes. Molecules that bind to the nucleosome, the complex of DNA and histone proteins, are key modulators of chromatin structure. Most recently, the formation of condensed chromatin regions based on phase-separation in the cell, a basic physical mechanism, was proposed. Increased understanding of the mechanisms of interaction between chromatin and lipids suggest that small lipid molecules, such as cholesterol and short-chain fatty acids, can regulate important nuclear functions...
April 17, 2018: Progress in Lipid Research
https://www.readbyqxmd.com/read/29676638/identification-of-novel-targets-for-lung-cancer-therapy-using-an-induced-pluripotent-stem-cell-model
#9
Vivek Shukla, Mahadev Rao, Hongen Zhang, Jeanette Beers, Darawalee Wangsa, Danny Wangsa, Floryne O Buishand, Yonghong Wang, Zhiya Yu, Holly Stevenson, Emily Reardon, Kaitlin C McLoughlin, Andrew Kaufman, Eden Payabyab, Julie A Hong, Mary Zhang, Sean R Davis, Daniel C Edelman, Guokai Chen, Markku Miettinen, Nicholas Restifo, Thomas Ried, Paul S Meltzer, David S Schrump
RATIONALE: Despite extensive studies, the genetic and epigenetic mechanisms that mediate initiation and progression of lung cancers have not been fully elucidated. Previously, we have demonstrated that via complementary mechanisms, including DNA methylation, polycomb repressive complexes, and noncoding RNAs, cigarette smoke induces stem-like phenotypes that coincide with progression to malignancy in normal respiratory epithelia as well as enhanced growth and metastatic potential of lung cancer cells...
April 2018: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/29674394/acetyl-coa-promotes-glioblastoma-cell-adhesion-and-migration-through-ca-2-nfat-signaling
#10
Joyce V Lee, Corbett T Berry, Karla Kim, Payel Sen, Taehyong Kim, Alessandro Carrer, Sophie Trefely, Steven Zhao, Sully Fernandez, Lauren E Barney, Alyssa D Schwartz, Shelly R Peyton, Nathaniel W Snyder, Shelley L Berger, Bruce D Freedman, Kathryn E Wellen
The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through which acetyl-CoA production impacts gene expression and its functional roles in promoting malignant phenotypes are poorly understood. Here, using histone H3 Lys27 acetylation (H3K27ac) ChIP-seq (chromatin immunoprecipitation [ChIP] coupled with next-generation sequencing) with normalization to an exogenous reference genome (ChIP-Rx), we found that changes in acetyl-CoA abundance trigger site-specific regulation of H3K27ac, correlating with gene expression as opposed to uniformly modulating this mark at all genes...
April 19, 2018: Genes & Development
https://www.readbyqxmd.com/read/29672586/selection-on-the-regulation-of-sympathetic-nervous-activity-in-humans-and-chimpanzees
#11
Kang Seon Lee, Paramita Chatterjee, Eun-Young Choi, Min Kyung Sung, Jaeho Oh, Hyejung Won, Seong-Min Park, Youn-Jae Kim, Soojin V Yi, Jung Kyoon Choi
Adrenergic α2C receptor (ADRA2C) is an inhibitory modulator of the sympathetic nervous system. Knockout mice for this gene show physiological and behavioural alterations that are associated with the fight-or-flight response. There is evidence of positive selection on the regulation of this gene during chicken domestication. Here, we find that the neuronal expression of ADRA2C is lower in human and chimpanzee than in other primates. On the basis of three-dimensional chromatin structure, we identified a cis-regulatory region whose DNA sequences have been significantly accelerated in human and chimpanzee...
April 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29661885/the-long-non-coding-rna-paupar-promotes-kap1-dependent-chromatin-changes-and-regulates-olfactory-bulb-neurogenesis
#12
Ioanna Pavlaki, Farah Alammari, Bin Sun, Neil Clark, Tamara Sirey, Sheena Lee, Dan J Woodcock, Chris P Ponting, Francis G Szele, Keith W Vance
Many long non-coding RNAs (lncRNAs) are expressed during central nervous system (CNS) development, yet their in vivo roles and mechanisms of action remain poorly understood. Paupar , a CNS-expressed lncRNA, controls neuroblastoma cell growth by binding and modulating the activity of transcriptional regulatory elements in a genome-wide manner. We show here that the Paupar lncRNA directly binds KAP1, an essential epigenetic regulatory protein, and thereby regulates the expression of shared target genes important for proliferation and neuronal differentiation...
April 16, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29658576/paclitaxel-suppresses-proliferation-and-induces-apoptosis-through-regulation-of-ros-and-the-akt-mapk-signaling-pathway-in-canine-mammary-gland-tumor-cells
#13
Xiaoli Ren, Bingbing Zhao, Hongjian Chang, Min Xiao, Yuhong Wu, Yun Liu
Paclitaxel is a diterpenoid compound, derived from the pacific yew (Taxus brevifolia) berry, which exhibits antineoplastic effects against various types of cancer. However, the antitumor effects and the molecular mechanisms of paclitaxel on canine CHMm cells remain to be elucidated. The aim of the present study was to investigate the antitumor effects of paclitaxel on CHMm cells and identify relevant signal transduction pathways modulated by paclitaxel using multiple methods including MTT assay, flow cytometry, acridine orange/ethidium bromide staining, transmission electron microscopy, determination of cellular reactive oxygen species (ROS), superoxide dismutase (SOD) and malondiadehyde (MDA) and western blotting, the data indicated that paclitaxel decreased cell viability, induced G2/M‑phase cell cycle arrest, suppressed the expression of cyclin B1 and induced apoptosis in a dose‑dependent manner...
April 11, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29656028/rice-transcription-factor-osdof11-modulates-sugar-transport-by-promoting-expression-of-sucrose-transporter-and-sweet-genes
#14
Yunfei Wu, Sang-Kyu Lee, Youngchul Yoo, Jinhuan Wei, Suk-Yoon Kwon, Sang-Won Lee, Jong-Seong Jeon, Gynheung An
Sucrose is produced in mesophyll cells and transferred into phloem cells before it is delivered long-distance to sink tissues. However, little is known about how sucrose transport is regulated in plants. Here, we identified T-DNA insertional mutants in Oryza sativa DNA BINDING WITH ONE FINGER 11 (OsDOF11), which is expressed in the vascular cells of photosynthetic organs and in various sink tissues. The osdof11 mutant plants are semi-dwarf and have fewer tillers and smaller panicles. Although sucrose enhanced root elongation in young wild-type (WT) seedlings, this did not occur in osdof11 seedlings due to reduced sucrose uptake...
April 12, 2018: Molecular Plant
https://www.readbyqxmd.com/read/29655483/chromatin-fiber-folding-directed-by-cooperative-histone-tail-acetylation-and-linker-histone-binding
#15
Gavin D Bascom, Tamar Schlick
In eukaryotic chromatin, islands of histone tail acetylation are found near transcription start sites and enhancers, whereas linker histones (LHs) are localized in intergenic regions with wild-type (WT) histone tails. However, the structural mechanisms by which acetylation, in combination with LH binding, modulates chromatin compaction and hence transcription regulation are unknown. To explore the folding propensity by which these features may govern gene expression, we analyze 20 kb fibers that contain regularly spaced acetylation islands of two sizes (2 or 5 kb) with various LH levels by mesoscale modeling...
April 11, 2018: Biophysical Journal
https://www.readbyqxmd.com/read/29648779/the-role-of-membrane-curvature-in-nanoscale-topography-induced-intracellular-signaling
#16
Hsin-Ya Lou, Wenting Zhao, Yongpeng Zeng, Bianxiao Cui
Over the past decade, there has been growing interest in developing biosensors and devices with nanoscale and vertical topography. Vertical nanostructures induce spontaneous cell engulfment, which enhances the cell-probe coupling efficiency and the sensitivity of biosensors. Although local membranes in contact with the nanostructures are found to be fully fluidic for lipid and membrane protein diffusions, cells appear to actively sense and respond to the surface topography presented by vertical nanostructures...
April 12, 2018: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29643506/structure-and-regulation-of-the-human-ino80-nucleosome-complex
#17
Rafael Ayala, Oliver Willhoft, Ricardo J Aramayo, Martin Wilkinson, Elizabeth A McCormack, Lorraine Ocloo, Dale B Wigley, Xiaodong Zhang
Access to DNA within nucleosomes is required for a variety of processes in cells including transcription, replication and repair. Consequently, cells encode multiple systems that remodel nucleosomes. These complexes can be simple, involving one or a few protein subunits, or more complicated multi-subunit machines 1 . Biochemical studies2-4 have placed the motor domains of several chromatin remodellers in the superhelical location 2 region of the nucleosome. Structural studies of yeast Chd1 and Snf2-a subunit in the complex with the capacity to remodel the structure of chromatin (RSC)-in complex with nucleosomes5-7 have provided insights into the basic mechanism of nucleosome sliding performed by these complexes...
April 11, 2018: Nature
https://www.readbyqxmd.com/read/29628309/jmjd6-licenses-er%C3%AE-dependent-enhancer-and-coding-gene-activation-by-modulating-the-recruitment-of-the-carm1-med12-co-activator-complex
#18
Wei-Wei Gao, Rong-Quan Xiao, Wen-Juan Zhang, Yi-Ren Hu, Bing-Ling Peng, Wen-Juan Li, Yao-Hui He, Hai-Feng Shen, Jian-Cheng Ding, Qi-Xuan Huang, Tian-Yi Ye, Ying Li, Zhi-Ying Liu, Rong Ding, Michael G Rosenfeld, Wen Liu
Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC-domain-containing proteins in mediating enhancer activation remain poorly understood. Here, we report that recruitment of the JmjC-domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 is found to interact with MED12 in the mediator complex to regulate its recruitment...
April 4, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29626056/methylindoles-and-methoxyindoles-are-agonists-and-antagonists-of-human-aryl-hydrocarbon-receptor-ahr
#19
Martina Stepankova, Iveta Bartonkova, Eva Jiskrova, Radim Vrzal, Sridhar Mani, Sandhya Kortagere, Zdenek Dvorak
Novel methyl-indoles were identified as endobiotic and xenobiotic ligands of human aryl hydrocarbon receptor (AhR). We examined the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhR. Employing reporter gene assays in AZ-AHR transgenic cells, we determined full agonist, partial agonist or antagonist activities of tested compounds, having substantially variable EC50 , IC50 and relative efficacies. The most effective agonists (EMAX relative to 5 nM dioxin) of AhR were 4-Me-indole (134%), 6-Me-indole (91%) and 7-MeO-indole (80%), respectively...
April 6, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29625794/the-role-of-epigenetic-therapies-in-colorectal-cancer
#20
REVIEW
Marina Baretti, Nilofer Saba Azad
Although developments in the diagnosis and therapy of colorectal cancer (CRC) have been made in the last decade, much work remains to be done as it remains the second leading cause of cancer death. It is now well established that epigenetic events, together with genetic alterations, are key events in initiation and progression of CRC. Epigenetics refers to heritable alterations in gene expression that do not involve changes in the DNA sequence. These alterations include DNA methylation, histone alterations, chromatin remodelers, and noncoding RNAs...
March 12, 2018: Current Problems in Cancer
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