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Designer chromatin

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https://www.readbyqxmd.com/read/28934465/regulation-of-chromatin-folding-by-conformational-variations-of-nucleosome-linker-dna
#1
Jenna M Buckwalter, Davood Norouzi, Anna Harutyunyan, Victor B Zhurkin, Sergei A Grigoryev
Linker DNA conformational variability has been proposed to direct nucleosome array folding into more or less compact chromatin fibers but direct experimental evidence for such models are lacking. Here, we tested this hypothesis by designing nucleosome arrays with A-tracts at specific locations in the nucleosome linkers to induce inward (AT-IN) and outward (AT-OUT) bending of the linker DNA. Using electron microscopy and analytical centrifugation techniques, we observed spontaneous folding of AT-IN nucleosome arrays into highly compact structures, comparable to those induced by linker histone H1...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28931929/a-resource-of-large-scale-molecular-markers-for-monitoring-agropyron-cristatum-chromatin-introgression-in-wheat-background-based-on-transcriptome-sequences
#2
Jinpeng Zhang, Weihua Liu, Yuqing Lu, Qunxing Liu, Xinming Yang, Xiuquan Li, Lihui Li
Agropyron cristatum is a wild grass of the tribe Triticeae and serves as a gene donor for wheat improvement. However, very few markers can be used to monitor A. cristatum chromatin introgressions in wheat. Here, we reported a resource of large-scale molecular markers for tracking alien introgressions in wheat based on transcriptome sequences. By aligning A. cristatum unigenes with the Chinese Spring reference genome sequences, we designed 9602 A. cristatum expressed sequence tag-sequence-tagged site (EST-STS) markers for PCR amplification and experimental screening...
September 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28931559/variation-in-position-effect-variegation-within-a-natural-population
#3
Keegan J P Kelsey, Andrew G Clark
Changes in chromatin state may drive changes in gene expression, and it is of growing interest to understand the population genetic forces that drive differences in chromatin state. Here, we use the phenomenon of position effect variegation (PEV), a well-studied proxy for chromatin state, to survey variation in PEV among a naturally derived population. Further, we explore the genetic architecture of natural variation in factors that modify PEV. While previous mutation screens have identified over 150 suppressors and enhancers of PEV, it remains unknown to what extent allelic variation in these modifiers mediate inter-individual variation in PEV...
September 20, 2017: Genetics
https://www.readbyqxmd.com/read/28926427/dna-methylation-targeted-drugs
#4
Elodie M Da Costa, Gabrielle McInnes, Annie Beaudry, Noël J-M Raynal
Targeting DNA hypermethylation, using nucleoside analogs, is an efficient approach to reprogram cancer cell epigenome leading to reduced proliferation, increased differentiation, recognition by the immune system, and ultimately cancer cell death. DNA methyltransferase inhibitors have been approved for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myelogenous leukemia. To improve clinical efficacy and overcome mechanisms of drug resistance, a second generation of DNA methyltransferase inhibitors has been designed and is currently in clinical trials...
September 2017: Cancer Journal
https://www.readbyqxmd.com/read/28926145/a-crispr-reimagining-new-twists-and-turns-of-crispr-beyond-the-genome-engineering-revolution
#5
Robert J Plummer, Yi Guo, Ying Peng
Despite its explosive applications in genome engineering, CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats) has been developed into a versatile tool beyond its well-known nuclease function. In this prospect article, we summarize a few exciting "off-label" applications of CRISPR including manipulating DNA sequences, visualizing chromosomal loci in living cells, and modulating transcription and chromatin structures. These novel applications will likely elevate CRISPR tools into yet another level of sophistication and diversity, leading to many more exciting cell biological discoveries...
September 19, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28923386/structure-based-design-synthesis-and-biological-evaluation-of-withaferin-a-analogues-as-potent-apoptotic-inducers
#6
Gabriel G Llanos, Liliana M Araujo, Ignacio A Jiménez, Laila M Moujir, Jaime Rodríguez, Carlos Jiménez, Isabel L Bazzocchi
Apoptosis inducers represent an attractive approach for the discovery and development of anticancer agents. Herein, we report on the development by molecular fine tuning of a withaferin A-based library of 63 compounds (2-64), 53 of them reported for the first time. Their antiproliferative evaluation on HeLa, A-549 and MCF-7 human tumor cell lines identified fifteen analogues displaying higher activity (IC50 values ranging 0.3-4.8 μM) than the lead (IC50 values ranging 1.3-10.1 μM) either in lag or log growth phases...
September 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28923333/buccal-cell-micronucleus-frequency-is-significantly-elevated-in-patients-with-spinocerebellar-ataxia-type-2
#7
Dany A Cuello-Almarales, Luis E Almaguer-Mederos, Yaimé Vázquez-Mojena, Dennis Almaguer-Gotay, Pedro Zayas-Feria, José M Laffita-Mesa, Yanetza González-Zaldívar, Raúl Aguilera-Rodríguez, Annelié Rodríguez-Estupiñán, Luis Velázquez-Pérez
Spinocerebellar ataxia type 2 (SCA2) is part of a group of at least nine dominantly inherited disorders characterized by progressive degeneration of specific neuronal populations and a shared mutational mechanism involving the expansion of a CAG repeat tract in coding regions of novel genes. Efforts have been made to identify biomarkers of disease progression, which would allow timely preventive therapeutic interventions. In the present study was assessed the influence of several genome instability biomarkers on SCA2 clinical severity...
April 2017: Archives of Medical Research
https://www.readbyqxmd.com/read/28922390/identifying-novel-transcription-factors-involved-in-the-inflammatory-response-by-using-binding-site-motif-scanning-in-genomic-regions-defined-by-histone-acetylation
#8
Peter S Askovich, Stephen A Ramsey, Alan H Diercks, Kathleen A Kennedy, Theo A Knijnenburg, Alan Aderem
The innate immune response to pathogenic challenge is a complex, multi-staged process involving thousands of genes. While numerous transcription factors that act as master regulators of this response have been identified, the temporal complexity of gene expression changes in response to pathogen-associated molecular pattern receptor stimulation strongly suggest that additional layers of regulation remain to be uncovered. The evolved pathogen response program in mammalian innate immune cells is understood to reflect a compromise between the probability of clearing the infection and the extent of tissue damage and inflammatory sequelae it causes...
2017: PloS One
https://www.readbyqxmd.com/read/28919484/lung-cancer-epigenetics-from-knowledge-to-applications
#9
REVIEW
Michaël Duruisseaux, Manel Esteller
Lung cancer is the leading cause of cancer-related mortality worldwide. Advances in our understanding of the genomics of lung cancer have led to substantial progress in the treatment of specific molecular subsets. Immunotherapy also emerges as a major breakthrough in lung cancer treatment. However, challenges remain as a consensual approach for early lung cancer detection remains elusive while primary or secondary drug resistance eventually leads to treatment failure in all patients with advanced disease. Furthermore, a large portion of patients are still treated with conventional chemotherapy that is only modestly effective...
September 14, 2017: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/28911922/neoadjuvant-sorafenib-gemcitabine-and-cisplatin-administration-preceding-cystectomy-in-patients-with-muscle-invasive-urothelial-bladder-carcinoma-an-open-label-single-arm-single-center-phase-2-study
#10
Andrea Necchi, Salvatore Lo Vullo, Daniele Raggi, Federica Perrone, Patrizia Giannatempo, Giuseppina Calareso, Elena Togliardi, Nicola Nicolai, Luigi Piva, Davide Biasoni, Mario Catanzaro, Tullio Torelli, Silvia Stagni, Maurizio Colecchia, Adele Busico, Marzia Pennati, Nadia Zaffaroni, Luigi Mariani, Roberto Salvioni
BACKGROUND: Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676). PATIENTS AND METHODS: After transurethral resection of the bladder, T2-T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400mg q12h daily, continuously, was added to standard GC chemotherapy...
September 11, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28895528/a-synthetic-biology-approach-to-probing-nucleosome-symmetry
#11
Yuichi Ichikawa, Caitlin F Connelly, Alon Appleboim, Thomas Cr Miller, Hadas Jacobi, Nebiyu A Abshiru, Hsin-Jung Chou, Yuanyuan Chen, Upasna Sharma, Yupeng Zheng, Paul M Thomas, Hsuiyi V Chen, Vineeta Bajaj, Christoph W Müller, Neil L Kelleher, Nir Friedman, Daniel Na Bolon, Oliver J Rando, Paul D Kaufman
The repeating subunit of chromatin, the nucleosome, includes two copies of each of the four core histones, and recent studies have reported that asymmetrically-modified nucleosomes occur at regulatory elements in vivo. To probe the mechanisms by which histone modifications are read , we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, which we extensively validated genetically and biochemically. Comparing effects of asymmetric histone tail point mutants with those of symmetric double mutants revealed that a single methylated H3K36 per nucleosome was sufficient to silence cryptic transcription in vivo...
September 12, 2017: ELife
https://www.readbyqxmd.com/read/28882223/micrornas-and-epigenetics
#12
Catia Moutinho, Manel Esteller
MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression mainly at the posttranscriptional level. Similar to protein-coding genes, their expression is also controlled by genetic and epigenetic mechanisms. Disruption of these control processes leads to abnormal expression of miRNAs in cancer. In this chapter, we discuss the supportive links between miRNAs and epigenetics in the context of carcinogenesis. miRNAs can be epigenetically regulated by DNA methylation and/or specific histone modifications...
2017: Advances in Cancer Research
https://www.readbyqxmd.com/read/28879853/dcas9-a-versatile-tool-for-epigenome-editing
#13
Daan J W Brocken, Mariliis Tark-Dame, Remus T Dame
The epigenome is a heritable layer of information not encoded in the DNA sequence of the genome, but in chemical modifications of DNA or histones. These chemical modifications, together with transcription factors, operate as spatiotemporal regulators of genome activity. Dissecting epigenome function requires controlled site-specific alteration of epigenetic information. Such control can be obtained using designed DNA-binding platforms associated with effector domains to function as targeted transcription factors or epigenetic modifiers...
September 7, 2017: Current Issues in Molecular Biology
https://www.readbyqxmd.com/read/28871329/transforming-growth-factor-%C3%AE-mediated-cd44-stat3-signaling-contributes-to-the-development-of-atrial-fibrosis-and-fibrillation
#14
Shang-Hung Chang, Yung-Hsin Yeh, Jia-Lin Lee, Yu-Juei Hsu, Chi-Tai Kuo, Wei-Jan Chen
Atrial fibrillation (AF) is associated with atrial fibrosis. Inhibition of atrial fibrosis might be a plausible approach for AF prevention and therapy. This study is designed to evaluate the potential role of CD44, a membrane receptor known to regulate fibrosis, and its related signaling in the pathogenesis of atrial fibrosis and AF. Treatment of cultured rat atrial fibroblasts with transforming growth factor-β (TGF-β, a key mediator of atrial fibrosis) led to a higher expression of hyaluronan (HA), CD44, STAT3, and collagen (a principal marker of fibrosis) than that of ventricular fibroblasts...
September 4, 2017: Basic Research in Cardiology
https://www.readbyqxmd.com/read/28864500/kr%C3%A3-ppel-like-factor-5-is-essential-for-maintenance-of-barrier-function-in-mouse-colon
#15
Yang Liu, Martyn Chidgey, Vincent W Yang, Agnieszka B Bialkowska
Krüppel-like factor 5 (KLF5) is a member of the zinc finger family of transcription factors that regulates homeostasis of the intestinal epithelium. Previous studies suggested an indispensable role of KLF5 in maintaining intestinal barrier function. In the current study, we investigated the mechanisms by which KLF5 regulates colonic barrier function in vivo and in vitro. We used an inducible and a constitutive intestine-specific Klf5 knockout mouse model (Villin-CreER(T2);Klf5(fl/fl) designated as Klf5(ΔIND) and Villin-Cre;Klf5(fl/fl) as Klf5(ΔIS) ), and studied an inducible KLF5 knockdown in Caco-2 BBe cells using a lentiviral Tet-on system (Caco-2 BBe KLF5ΔIND)...
September 1, 2017: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/28860350/identification-of-distinct-mutational-patterns-and-new-driver-genes-in-oesophageal-squamous-cell-carcinomas-and-adenocarcinomas
#16
De-Chen Lin, Huy Q Dinh, Jian-Jun Xie, Anand Mayakonda, Tiago Chedraoui Silva, Yan-Yi Jiang, Ling-Wen Ding, Jian-Zhong He, Xiu-E Xu, Jia-Jie Hao, Ming-Rong Wang, Chunquan Li, Li-Yan Xu, En-Min Li, Benjamin P Berman, H Phillip Koeffler
OBJECTIVES: Oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC) are distinct cancers in terms of a number of clinical and epidemiological characteristics, complicating the design of clinical trials and biomarker developments. We analysed 1048 oesophageal tumour-germline pairs from both subtypes, to characterise their genomic features, and biological and clinical significance. DESIGN: Previously exome-sequenced samples were re-analysed to identify significantly mutated genes (SMGs) and mutational signatures...
August 31, 2017: Gut
https://www.readbyqxmd.com/read/28859663/sparse-conserved-under-methylated-cpgs-are-associated-with-high-order-chromatin-structure
#17
Xueqiu Lin, Jianzhong Su, Kaifu Chen, Benjamin Rodriguez, Wei Li
BACKGROUND: Whole-genome bisulfite sequencing (WGBS) is the gold standard for studying landscape DNA methylation. Current computational methods for WGBS are mainly designed for gene regulatory regions with multiple under-methylated CpGs (UMCs), such as promoters and enhancers. RESULTS: To reliably predict the functional importance of single isolated UMCs across the genome, which is usually not achievable using traditional methods, we develop a multi-sample-based method...
August 31, 2017: Genome Biology
https://www.readbyqxmd.com/read/28855339/role-of-remodeling-and-spacing-factor-1-in-histone-h2a-ubiquitination-mediated-gene-silencing
#18
Zhuo Zhang, Amanda E Jones, Wei Wu, Jinman Kim, Yue Kang, Xiaobao Bi, Yue Gu, Ivan K Popov, Matthew B Renfrow, Marina N Vassylyeva, Dmitry G Vassylyev, Keith E Giles, Dongquan Chen, Ashwath Kumar, Yuhong Fan, Yufeng Tong, Chuan-Fa Liu, Woojin An, Chenbei Chang, Jianjun Luo, Louise T Chow, Hengbin Wang
Posttranslational histone modifications play important roles in regulating chromatin-based nuclear processes. Histone H2AK119 ubiquitination (H2Aub) is a prevalent modification and has been primarily linked to gene silencing. However, the underlying mechanism remains largely obscure. Here we report the identification of RSF1 (remodeling and spacing factor 1), a subunit of the RSF complex, as a H2Aub binding protein, which mediates the gene-silencing function of this histone modification. RSF1 associates specifically with H2Aub, but not H2Bub nucleosomes, through a previously uncharacterized and obligatory region designated as ubiquitinated H2A binding domain...
August 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28855099/epigenetics-in-chronic-liver-disease
#19
REVIEW
Marie Boyle, Jelena Mann
Elucidation of the fundamental epigenetic mechanisms governing gene expression and cellular phenotype in the past decade has provided novel insights into the epigenetic modulation of chronic liver disease. While genetic factors are undoubtedly important, the opportunity afforded by exploitation of the "fine-tuning" epigenetic mechanisms promises to drive forward an unprecedented advance in precision medicine within hepatology. The current challenges remain to improve diagnostics, prognostics and develop personalised therapy...
August 27, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28841465/design-of-a-nanocomposite-substrate-inducing-adult-stem-cell-assembly-and-progression-toward-an-epiblast-like-or-primitive-endoderm-like-phenotype-via-mechanotransduction
#20
Francesco Morena, Ilaria Armentano, Pia Montanucci, Chiara Argentati, Elena Fortunati, Simona Montesano, Ilaria Bicchi, Teresa Pescara, Ilaria Pennoni, Samantha Mattioli, Luigi Torre, Loredana Latterini, Carla Emiliani, Giuseppe Basta, Riccardo Calafiore, Josè Maria Kenny, Sabata Martino
This work shows that the active interaction between human umbilical cord matrix stem cells and Poly (l-lactide)acid (PLLA) and PLLA/Multi Walled Carbon Nanotubes (MWCNTs) nanocomposite films results in the stem cell assembly as a spheroid conformation and affects the stem cell fate transition. We demonstrated that spheroids directly respond to a tunable surface and the bulk properties (electric, dielectric and thermal) of plain and nanocomposite PLLA films by triggering a mechanotransduction axis. This stepwise process starts from tethering of the cells' focal adhesion proteins to the surface, together with the adherens junctions between cells...
August 16, 2017: Biomaterials
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