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small molecule Chip-seq

Chong Wang, Hufeng Zhou, Yong Xue, Jun Liang, Yohei Narita, Catherine Gerdt, Amy Y Zheng, Runsheng Jiang, Stephen Trudeau, Chih-Wen Peng, Benjamin E Gewurz, Bo Zhao
Epstein-Barr virus nuclear antigen (EBNA) leader protein (EBNALP) is one of the first viral genes expressed upon B-cell infection. EBNALP is essential for EBV-mediated B-cell immortalization. EBNALP is thought to function primarily by coactivating EBNA2-mediated transcription. Chromatin immune precipitation followed by deep sequencing (ChIP-seq) studies highlight that EBNALP frequently cooccupies DNA sites with host cell transcription factors (TFs), in particular, EP300, implicating a broader role in transcription regulation...
May 1, 2018: Journal of Virology
Daniel Castellano-Castillo, Pierre-Damien Denechaud, Isabel Moreno-Indias, Francisco Tinahones, Lluis Fajas, María Isabel Queipo-Ortuño, Fernando Cardona
Chromatin immunoprecipitation (ChIP) has gained importance to identify links between the genome and the proteome. Adipose tissue has emerged as an active tissue, which secretes a wide range of molecules that have been related to metabolic and obesity-related disorders, such as diabetes, cardiovascular failure, metabolic syndrome, or cancer. In turn, epigenetics has raised the importance in discerning the possible relationship between metabolic disorders, lifestyle and environment. However, ChIP application in human adipose tissue is limited by several factors, such as sample size, frozen sample availability, high lipid content and cellular composition of the tissue...
2018: PloS One
Benjamin R Leadem, Ioannis Kagiampakis, Catherine Wilson, Tommy K Cheung, David Arnott, Patrick Trojer, Marie Classon, Hariharan Easwaran, Stephen B Baylin
The H3K4 demethylase KDM5B is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes...
December 27, 2017: Cancer Research
Shyam Nathan, Yongxian Ma, York A Tomita, Eliseu De Oliveira, Milton L Brown, Eliot M Rosen
PURPOSE: We previously identified small molecules that fit into a BRCA1-binding pocket within estrogen receptor-alpha (ERα), mimic the ability of BRCA1 to inhibit ERα activity ("BRCA1-mimetics"), and overcome antiestrogen resistance. One such compound, the hydrochloride salt of NSC35446 ("NSC35446.HCl"), also inhibited the growth of antiestrogen-resistant LCC9 tumor xenografts. The purpose of this study was to investigate the down-stream effects of NSC35446.HCl and its mechanism of action...
December 2017: Breast Cancer Research and Treatment
Yang Li, Jin Wang, Jie Yin, Xinhua Liu, Minghang Yu, Ting Li, Han Yan, Xi Wang
Studies of Natural Killer (NK) cell cytotoxicity have mainly focused on the balance of activating and inhibitory receptors, signaling transduction, calcium influx, formation of immune synapse, and cytolytic degranulation. However, little is known about the chromatin state of NK cells and the impact of its changes during target recognition. In this study, we investigate the contribution of chromatin state dynamics during NK cell activation by comprehensively analyzing a set of microarray data and two sets of Chromatin Immunoprecipitation-Sequencing (ChIP-seq) data...
June 27, 2017: Oncotarget
Tomoko Ohashi, Masashi Idogawa, Yasushi Sasaki, Takashi Tokino
The tumor suppressor gene p53 is frequently mutated in human cancer. p53 executes various functions, such as apoptosis induction and cell cycle arrest, by modulating transcriptional regulation. In this study, LIM domain and Actin-binding protein 1 (LIMA1) was identified as a target of the p53 family using a cDNA microarray. We also evaluated genome-wide occupancy of the p53 protein by performing chromatin immunoprecipitation-sequencing (ChIP-seq) and identified two p53 response elements in the LIMA1 gene. LIMA1 protein levels were increased by treatment with nutlin-3a, a small molecule that activates endogenous p53...
April 1, 2017: Cancer Letters
Cédric Deluz, Elias T Friman, Daniel Strebinger, Alexander Benke, Mahé Raccaud, Andrea Callegari, Marion Leleu, Suliana Manley, David M Suter
Mitotic bookmarking transcription factors remain bound to chromosomes during mitosis and were proposed to regulate phenotypic maintenance of stem and progenitor cells at the mitosis-to-G1 (M-G1) transition. However, mitotic bookmarking remains largely unexplored in most stem cell types, and its functional relevance for cell fate decisions remains unclear. Here we screened for mitotic chromosome binding within the pluripotency network of embryonic stem (ES) cells and show that SOX2 and OCT4 remain bound to mitotic chromatin through their respective DNA-binding domains...
November 15, 2016: Genes & Development
Takahiro Sato, Matteo Cesaroni, Woonbok Chung, Shoghag Panjarian, Anthony Tran, Jozef Madzo, Yasuyuki Okamoto, Hanghang Zhang, Xiaowei Chen, Jaroslav Jelinek, Jean-Pierre J Issa
A central challenge in the development of epigenetic cancer therapy is the ability to direct selectivity in modulating gene expression for disease-selective efficacy. To address this issue, we characterized by RNA-seq, DNA methylation, and ChIP-seq analyses the epigenetic response of a set of colon, breast, and leukemia cancer cell lines to small-molecule inhibitors against DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343)...
January 15, 2017: Cancer Research
Brian Egan, Chih-Chi Yuan, Madeleine Lisa Craske, Paul Labhart, Gulfem D Guler, David Arnott, Tobias M Maile, Jennifer Busby, Chisato Henry, Theresa K Kelly, Charles A Tindell, Suchit Jhunjhunwala, Feng Zhao, Charlie Hatton, Barbara M Bryant, Marie Classon, Patrick Trojer
Chromatin immunoprecipitation and DNA sequencing (ChIP-seq) has been instrumental in inferring the roles of histone post-translational modifications in the regulation of transcription, chromatin compaction and other cellular processes that require modulation of chromatin structure. However, analysis of ChIP-seq data is challenging when the manipulation of a chromatin-modifying enzyme significantly affects global levels of histone post-translational modifications. For example, small molecule inhibition of the methyltransferase EZH2 reduces global levels of histone H3 lysine 27 trimethylation (H3K27me3)...
2016: PloS One
Geoffrey Liu, Sinead Cuffe, Shermi Liang, Abul Kalam Azad, Lu Cheng, Yonathan Brhane, Xin Qiu, David W Cescon, Jeffrey Bruce, Zhuo Chen, Dangxiao Cheng, Devalben Patel, Brandon C Tse, Scott A Laurie, Glenwood Goss, Natasha B Leighl, Rayjean Hung, Penelope A Bradbury, Lesley Seymour, Frances A Shepherd, Ming Sound Tsao, Bingshu E Chen, Wei Xu, David N Reisman
Introduction: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene that is silenced in 15% of non-small cell lung cancer (NSCLC). Two novel BRM promoter polymorphisms ( BRM -741 and BRM -1321) are associated with reversible epigenetic silencing of BRM protein expression. Experimental Design: Advanced NSCLC patients from the Princess Margaret (PM) cohort study and from the CCTG BR.24 clinical trial were genotyped for BRM promoter polymorphisms. Associations of BRM variants with survival were assessed using log-rank tests, the method of Kaplan and Meier, and Cox proportional hazards models...
May 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Daniel Beck, Jenny Zobel, Ruth Barber, Sian Evans, Larissa Lezina, Rebecca L Allchin, Matthew Blades, Richard Elliott, Christopher J Lord, Alan Ashworth, Andrew C G Porter, Simon D Wagner
We demonstrate the usefulness of synthetic lethal screening of a conditionally BCL6-deficient Burkitt lymphoma cell line, DG75-AB7, with a library of small molecules to determine survival pathways suppressed by BCL6 and suggest mechanism-based treatments for lymphoma. Lestaurtinib, a JAK2 inhibitor and one of the hits from the screen, repressed survival of BCL6-deficient cells in vitro and reduced growth and proliferation of xenografts in vivo BCL6 deficiency in DG75-AB7 induced JAK2 mRNA and protein expression and STAT3 phosphorylation...
August 5, 2016: Journal of Biological Chemistry
Kaitlyn M Gayvert, Etienne Dardenne, Cynthia Cheung, Mary Regina Boland, Tal Lorberbaum, Jackline Wanjala, Yu Chen, Mark A Rubin, Nicholas P Tatonetti, David S Rickman, Olivier Elemento
Mutations in transcription factor (TF) genes are frequently observed in tumors, often leading to aberrant transcriptional activity. Unfortunately, TFs are often considered undruggable due to the absence of targetable enzymatic activity. To address this problem, we developed CRAFTT, a computational drug-repositioning approach for targeting TF activity. CRAFTT combines ChIP-seq with drug-induced expression profiling to identify small molecules that can specifically perturb TF activity. Application to ENCODE ChIP-seq datasets revealed known drug-TF interactions, and a global drug-protein network analysis supported these predictions...
June 14, 2016: Cell Reports
B Mitton, H-D Chae, K Hsu, R Dutta, G Aldana-Masangkay, R Ferrari, K Davis, B C Tiu, A Kaul, N Lacayo, G Dahl, F Xie, B X Li, M R Breese, E M Landaw, G Nolan, M Pellegrini, S Romanov, X Xiao, K M Sakamoto
The transcription factor CREB (cAMP Response-Element Binding Protein) is overexpressed in the majority of acute myeloid leukemia (AML) patients, and this is associated with a worse prognosis. Previous work revealed that CREB overexpression augmented AML cell growth, while CREB knockdown disrupted key AML cell functions in vitro. In contrast, CREB knockdown had no effect on long-term hematopoietic stem cell activity in mouse transduction/transplantation assays. Together, these studies position CREB as a promising drug target for AML...
December 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Marjolein Droog, Ekaterina Nevedomskaya, Yongsoo Kim, Tesa Severson, Koen D Flach, Mark Opdam, Karianne Schuurman, Patrycja Gradowska, Michael Hauptmann, Gwen Dackus, Harry Hollema, Marian Mourits, Petra Nederlof, Hester van Boven, Sabine C Linn, Lodewyk Wessels, Flora E van Leeuwen, Wilbert Zwart
Tamoxifen, a small-molecule antagonist of the transcription factor estrogen receptor alpha (ERα) used to treat breast cancer, increases risks of endometrial cancer. However, no parallels of ERα transcriptional action in breast and endometrial tumors have been found that might explain this effect. In this study, we addressed this issue with a genome-wide assessment of ERα-chromatin interactions in surgical specimens obtained from patients with tamoxifen-associated endometrial cancer. ERα was found at active enhancers in endometrial cancer cells as marked by the presence of RNA polymerase II and the histone marker H3K27Ac...
July 1, 2016: Cancer Research
Yan-Yi Jiang, De-Chen Lin, Anand Mayakonda, Masaharu Hazawa, Ling-Wen Ding, Wen-Wen Chien, Liang Xu, Ye Chen, Jin-Fen Xiao, William Senapedis, Erkan Baloglu, Deepika Kanojia, Li Shang, Xin Xu, Henry Yang, Jeffrey W Tyner, Ming-Rong Wang, H Phillip Koeffler
OBJECTIVES: Oesophageal squamous cell carcinoma (OSCC) is an aggressive malignancy and the major histological subtype of oesophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of OSCC, few targetable genomic lesions have been identified, and no molecular therapy is available. This study aims to identify druggable candidates in this tumour. DESIGN: High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds...
August 2017: Gut
Christopher L Frank, Dinesh Manandhar, Raluca Gordân, Gregory E Crawford
BACKGROUND: Small molecule inhibitors of histone deacetylases (HDACi) hold promise as anticancer agents for particular malignancies. However, clinical use is often confounded by toxicity, perhaps due to indiscriminate hyperacetylation of cellular proteins. Therefore, elucidating the mechanisms by which HDACi trigger differentiation, cell cycle arrest, or apoptosis of cancer cells could inform development of more targeted therapies. We used the myelogenous leukemia line K562 as a model of HDACi-induced differentiation to investigate chromatin accessibility (DNase-seq) and expression (RNA-seq) changes associated with this process...
2016: Epigenetics & Chromatin
Maria-Paz Garcia-Cuellar, Christian Büttner, Christoph Bartenhagen, Martin Dugas, Robert K Slany
MLL fusions are leukemogenic transcription factors that enhance transcriptional elongation through modification of chromatin and RNA Pol II. Global transcription rates and chromatin changes accompanying the transformation process induced by MLL-ENL were monitored by nascent RNA-seq and ChIP-seq, revealing 165 direct target genes separated into two distinct clades. ME5 genes bound MLL-ENL at the promoter, relied on DOT1L-mediated histone methylation, and coded preferentially for transcription factors, including many homeobox genes...
April 12, 2016: Cell Reports
Philipp Tropberger, Alexandre Mercier, Margaret Robinson, Weidong Zhong, Don E Ganem, Meghan Holdorf
Chronic hepatitis B virus (HBV) infection affects 240 million people worldwide and is a major risk factor for liver failure and hepatocellular carcinoma. Current antiviral therapy inhibits cytoplasmic HBV genomic replication, but is not curative because it does not directly affect nuclear HBV closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence. Novel approaches that directly target cccDNA regulation would therefore be highly desirable. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications (PTMs)...
October 20, 2015: Proceedings of the National Academy of Sciences of the United States of America
Erika L Moen, Edward Litwin, Stephen Arnovitz, Xu Zhang, Wei Zhang, M Eileen Dolan, Lucy A Godley
In many whole genome studies of gene expression or modified cytosines, data from probes localized to the X-chromosome are removed from analyses due to gender bias. Previously, we observed population differences in cytosine modifications between Caucasian and African lymphoblastoid cell lines (LCLs) on the autosomes using whole genome arrays to measure modified cytosines. DNA methylation plays a critical role in establishment and maintenance of X-chromosome inactivation in females. Therefore, we reasoned that by investigating cytosine modification patterns specifically on the X-chromosome, we could obtain valuable information about a chromosome that is often disregarded in genome-wide analyses...
2015: Epigenetics: Official Journal of the DNA Methylation Society
Jialiang Wang, Ying Wu, Feng Zhao, Yuting Wu, Wei Dong, Jue Zhao, Zuoyan Zhu, Dong Liu
Fibroblast growth factors (Fgfs) play important roles in developmental processes of the inner ear, including the ontogeny of the statoacoustic ganglia (SAG) and hair cells. However, the detailed genetic mechanism(s) underlying Fgf/Fgfr-dependent otic neural development remains elusive. Using conditional genetic approaches and inhibitory small molecules, we have revealed that Fgfr-PI3K/Akt signaling is mainly responsible for zebrafish SAG development and have determined that Sox9a and Atoh1a act downstream of Fgfr-Akt signaling to specify and/or maintain the otic neuron fate during the early segmentation stage...
January 7, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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