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small molecule Chip-seq

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https://www.readbyqxmd.com/read/27920086/a-role-for-mitotic-bookmarking-of-sox2-in-pluripotency-and-differentiation
#1
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...
December 5, 2016: Genes & Development
https://www.readbyqxmd.com/read/27879268/transcriptional-selectivity-of-epigenetic-therapy-in-cancer
#2
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)...
November 22, 2016: Cancer Research
https://www.readbyqxmd.com/read/27875550/an-alternative-approach-to-chip-seq-normalization-enables-detection-of-genome-wide-changes-in-histone-h3-lysine-27-trimethylation-upon-ezh2-inhibition
#3
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
https://www.readbyqxmd.com/read/27827316/brm-promoter-polymorphisms-risk-and-survival-of-advanced-non-small-cell-lung-cancer-patients-in-the-princess-margaret-cohort-and-ncic-ctg-br-24-trial
#4
Geoffrey Liu, Sinead Cuffe, Shermi Liang, Abul K Azad, Lu Cheng, Yonathan Brhane, Xin Qiu, David W Cescon, Jeff P Bruce, Zhuo Chen, Dangxiao Cheng, Devalben Patel, Brandon C Tse, Scott A Laurie, Glenwood D Goss, Natasha B Leighl, Rayjean J Hung, Penelope A Bradbury, Lesley Seymour, Frances A Shepherd, Ming-Sound Tsao, Bingshu E Chen, Wei Xu, David Reisman
PURPOSE: 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, 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...
November 8, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27268052/synthetic-lethal-screen-demonstrates-that-a-jak2-inhibitor-suppresses-a-bcl6-dependent-il10ra-jak2-stat3-pathway-in-high-grade-b-cell-lymphoma
#5
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
https://www.readbyqxmd.com/read/27264179/a-computational-drug-repositioning-approach-for-targeting-oncogenic-transcription-factors
#6
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
https://www.readbyqxmd.com/read/27211267/small-molecule-inhibition-of-camp-response-element-binding-protein-in-human-acute-myeloid-leukemia-cells
#7
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
https://www.readbyqxmd.com/read/27197147/comparative-cistromics-reveals-genomic-cross-talk-between-foxa1-and-er%C3%AE-in-tamoxifen-associated-endometrial-carcinomas
#8
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
https://www.readbyqxmd.com/read/27196599/targeting-super-enhancer-associated-oncogenes-in-oesophageal-squamous-cell-carcinoma
#9
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...
May 10, 2016: Gut
https://www.readbyqxmd.com/read/27087856/hdac-inhibitors-cause-site-specific-chromatin-remodeling-at-pu-1-bound-enhancers-in-k562-cells
#10
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
https://www.readbyqxmd.com/read/27050521/leukemogenic-mll-enl-fusions-induce-alternative-chromatin-states-to-drive-a-functionally-dichotomous-group-of-target-genes
#11
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
https://www.readbyqxmd.com/read/26438841/mapping-of-histone-modifications-in-episomal-hbv-cccdna-uncovers-an-unusual-chromatin-organization-amenable-to-epigenetic-manipulation
#12
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
https://www.readbyqxmd.com/read/26178744/characterization-of-cpg-sites-that-escape-methylation-on-the-inactive-human-x-chromosome
#13
COMPARATIVE STUDY
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
https://www.readbyqxmd.com/read/25568117/fgf-signaling-dependent-sox9a-and-atoh1a-regulate-otic-neural-development-in-zebrafish
#14
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
https://www.readbyqxmd.com/read/25561494/stably-paused-genes-revealed-through-inhibition-of-transcription-initiation-by-the-tfiih-inhibitor-triptolide
#15
Fei Chen, Xin Gao, Ali Shilatifard
Transcription by RNA polymerase II (Pol II) in metazoans is regulated in several steps, including preinitiation complex (PIC) formation, initiation, Pol II escape, productive elongation, cotranscriptional RNA processing, and termination. Genome-wide studies have demonstrated that the phenomenon of promoter-bound Pol II pausing is widespread, especially for genes involved in developmental and stimulus-responsive pathways. However, a mechanistic understanding of the paused Pol II state at promoters is limited...
January 1, 2015: Genes & Development
https://www.readbyqxmd.com/read/25387393/suppression-of-the-foxm1-transcriptional-programme-via-novel-small-molecule-inhibition
#16
Michael V Gormally, Thomas S Dexheimer, Giovanni Marsico, Deborah A Sanders, Christopher Lowe, Dijana Matak-Vinković, Sam Michael, Ajit Jadhav, Ganesha Rai, David J Maloney, Anton Simeonov, Shankar Balasubramanian
The transcription factor FOXM1 binds to sequence-specific motifs on DNA (C/TAAACA) through its DNA-binding domain (DBD) and activates proliferation- and differentiation-associated genes. Aberrant overexpression of FOXM1 is a key feature in oncogenesis and progression of many human cancers. Here--from a high-throughput screen applied to a library of 54,211 small molecules--we identify novel small molecule inhibitors of FOXM1 that block DNA binding. One of the identified compounds, FDI-6 (NCGC00099374), is characterized in depth and is shown to bind directly to FOXM1 protein, to displace FOXM1 from genomic targets in MCF-7 breast cancer cells, and induce concomitant transcriptional downregulation...
November 12, 2014: Nature Communications
https://www.readbyqxmd.com/read/25311424/unravelling-the-genomic-targets-of-small-molecules-using-high-throughput-sequencing
#17
REVIEW
Raphaël Rodriguez, Kyle M Miller
Small molecules--including various approved and novel cancer therapeutics--can operate at the genomic level by targeting the DNA and protein components of chromatin. Emerging evidence suggests that functional interactions between small molecules and the genome are non-stochastic and are influenced by a dynamic interplay between DNA sequences and chromatin states. The establishment of genome-wide maps of small-molecule targets using unbiased methodologies can help to characterize and exploit drug responses. In this Review, we discuss how high-throughput sequencing strategies, such as ChIP-seq (chromatin immunoprecipitation followed by sequencing) and Chem-seq (chemical affinity capture and massively parallel DNA sequencing), are enabling the comprehensive identification of small-molecule target sites throughout the genome, thereby providing insights into unanticipated drug effects...
December 2014: Nature Reviews. Genetics
https://www.readbyqxmd.com/read/25204781/single-molecule-and-single-cell-epigenomics
#18
REVIEW
Byung-Ryool Hyun, John L McElwee, Paul D Soloway
Dynamically regulated changes in chromatin states are vital for normal development and can produce disease when they go awry. Accordingly, much effort has been devoted to characterizing these states under normal and pathological conditions. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) is the most widely used method to characterize where in the genome transcription factors, modified histones, modified nucleotides and chromatin binding proteins are found; bisulfite sequencing (BS-seq) and its variants are commonly used to characterize the locations of DNA modifications...
January 15, 2015: Methods: a Companion to Methods in Enzymology
https://www.readbyqxmd.com/read/24928520/chem-seq-permits-identification-of-genomic-targets-of-drugs-against-androgen-receptor-regulation-selected-by-functional-phenotypic-screens
#19
Chunyu Jin, Liuqing Yang, Min Xie, Chunru Lin, Daria Merkurjev, Joy C Yang, Bogdan Tanasa, Soohwan Oh, Jie Zhang, Kenneth A Ohgi, Hongyan Zhou, Wenbo Li, Christopher P Evans, Sheng Ding, Michael G Rosenfeld
Understanding the mechanisms by which compounds discovered using cell-based phenotypic screening strategies might exert their effects would be highly augmented by new approaches exploring their potential interactions with the genome. For example, altered androgen receptor (AR) transcriptional programs, including castration resistance and subsequent chromosomal translocations, play key roles in prostate cancer pathological progression, making the quest for identification of new therapeutic agents and an understanding of their actions a continued priority...
June 24, 2014: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/24551185/computational-characterization-of-modes-of-transcriptional-regulation-of-nuclear-receptor-genes
#20
Yogita Sharma, Chandra Sekhar Reddy Chilamakuri, Marit Bakke, Boris Lenhard
BACKGROUND: Nuclear receptors are a large structural class of transcription factors that act with their co-regulators and repressors to maintain a variety of biological and physiological processes such as metabolism, development and reproduction. They are activated through the binding of small ligands, which can be replaced by drug molecules, making nuclear receptors promising drug targets. Transcriptional regulation of the genes that encode them is central to gaining a deeper understanding of the diversity of their biochemical and biophysical roles and their role in disease and therapy...
2014: PloS One
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