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https://www.readbyqxmd.com/read/28809015/systems-biology-analyses-in-chicken-workflow-for-transcriptome-and-chip-seq-analyses-using-the-chicken-skin-paradigm
#1
Yung-Chih Lai, Randall B Widelitz, Cheng-Ming Chuong
With advances in molecular biology, various biological phenomena can now be explored at higher resolution using mRNA sequencing (RNA-Seq) and chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq), two powerful high-throughput next-generation sequencing (NGS) technologies. While methods are used widely in mouse, human, etc., less information is available in other animals, such as the chicken. Here we assemble a workflow of the RNA-Seq and ChIP-Seq analyses for the chicken studies using chicken skin appendage tissue as an example...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28807940/mitotic-vulnerability-in-triple-negative-breast-cancer-associated-with-lin9-is-targetable-with-bet-inhibitors
#2
Jennifer M Sahni, Sylvia S Gayle, Bryan Webb, Kristen L Weber-Bonk, Darcie D Seachrist, Salendra Singh, Steven T Sizemore, Nicole A Restrepo, Gurkan Bebek, Peter Scacheri, Vinay Varadan, Matthew K Summers, Ruth A Keri
Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of Bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe...
August 14, 2017: Cancer Research
https://www.readbyqxmd.com/read/28741488/extraordinary-cancer-epigenomics-thinking-outside-the-classical-coding-and-promoter-box
#3
REVIEW
Matthew Murtha, Manel Esteller
The advent of functional genomics powered by high-throughput sequencing has given us a new appreciation of the genomic sequences that lie outside the canonical promoter-coding sequence box. These regions harbor distant regulatory elements, enhancers, super-enhancers, insulators, alternative promoters, and sequences that transcribe as noncoding RNAs (ncRNAs) such as miRNAs and long ncRNAs. These functional genomics studies have also enabled a clearer understanding of the role of the 3D structure of the genome in epigenetic regulation...
October 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28740262/heterogeneity-of-neuroblastoma-cell-identity-defined-by-transcriptional-circuitries
#4
Valentina Boeva, Caroline Louis-Brennetot, Agathe Peltier, Simon Durand, Cécile Pierre-Eugène, Virginie Raynal, Heather C Etchevers, Sophie Thomas, Alban Lermine, Estelle Daudigeos-Dubus, Birgit Geoerger, Martin F Orth, Thomas G P Grünewald, Elise Diaz, Bertrand Ducos, Didier Surdez, Angel M Carcaboso, Irina Medvedeva, Thomas Deller, Valérie Combaret, Eve Lapouble, Gaelle Pierron, Sandrine Grossetête-Lalami, Sylvain Baulande, Gudrun Schleiermacher, Emmanuel Barillot, Hermann Rohrer, Olivier Delattre, Isabelle Janoueix-Lerosey
Neuroblastoma is a tumor of the peripheral sympathetic nervous system, derived from multipotent neural crest cells (NCCs). To define core regulatory circuitries (CRCs) controlling the gene expression program of neuroblastoma, we established and analyzed the neuroblastoma super-enhancer landscape. We discovered three types of identity in neuroblastoma cell lines: a sympathetic noradrenergic identity, defined by a CRC module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs); an NCC-like identity, driven by a CRC module containing AP-1 TFs; and a mixed type, further deconvoluted at the single-cell level...
July 24, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28740110/neuroblastoma-tumours-get-super-enhanced
#5
Conor A Bradley
No abstract text is available yet for this article.
July 25, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28729405/super-enhancer-analysis-defines-novel-epigenomic-subtypes-of-non-apl-aml-including-an-rar%C3%AE-dependency-targetable-by-sy-1425-a-potent-and-selective-rar%C3%AE-agonist
#6
Michael R McKeown, M Ryan Corces, Matthew L Eaton, Chris Fiore, Emily Lee, Jeremy T Lopez, Mei Wei Chen, Darren Smith, Steven M Chan, Julie L Koenig, Kathryn Austgen, Matt G Guenther, David A Orlando, Jakob Lovén, Christian C Fritz, Ravindra Majeti
We characterized the enhancer landscape of 66 AML patients, identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their super-enhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong super-enhancer at the retinoic acid receptor alpha (RARA) gene locus. Presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene)...
July 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28720843/clinical-study-of-genomic-drivers-in-pancreatic-ductal-adenocarcinoma
#7
Michael T Barrett, Ray Deiotte, Elizabeth Lenkiewicz, Smriti Malasi, Tara Holley, Lisa Evers, Richard G Posner, Timothy Jones, Haiyong Han, Mark Sausen, Victor E Velculescu, Jeffrey Drebin, Peter O'Dwyer, Gayle Jameson, Ramesh K Ramanathan, Daniel D Von Hoff
BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. METHODS: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples...
August 8, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28718439/super-enhancer-driven-transcriptional-dependencies-in-cancer
#8
Satyaki Sengupta, Rani E George
Transcriptional deregulation is one of the core tenets of cancer biology and is underpinned by alterations in both protein-coding genes and noncoding regulatory elements. Large regulatory elements, so-called super-enhancers (SEs), are central to the maintenance of cancer cell identity and promote oncogenic transcription to which cancer cells become highly addicted. Such dependence on SE-driven transcription for proliferation and survival offers an Achilles heel for the therapeutic targeting of cancer cells...
April 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28714474/facultative-ctcf-sites-moderate-mammary-super-enhancer-activity-and-regulate-juxtaposed-gene-in-non-mammary-cells
#9
M Willi, K H Yoo, F Reinisch, T M Kuhns, H K Lee, C Wang, L Hennighausen
Precise spatiotemporal gene regulation is paramount for the establishment and maintenance of cell-specific programmes. Although there is evidence that chromatin neighbourhoods, formed by the zinc-finger protein CTCF, can sequester enhancers and their target genes, there is limited in vivo evidence for CTCF demarcating super-enhancers and preventing cross talk between distinct regulatory elements. Here, we address these questions in the Wap locus with its mammary-specific super-enhancer separated by CTCF sites from widely expressed genes...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28703137/platelet-function-is-modified-by-common-sequence-variation-in-megakaryocyte-super-enhancers
#10
Romina Petersen, John J Lambourne, Biola M Javierre, Luigi Grassi, Roman Kreuzhuber, Dace Ruklisa, Isabel M Rosa, Ana R Tomé, Heather Elding, Johanna P van Geffen, Tao Jiang, Samantha Farrow, Jonathan Cairns, Abeer M Al-Subaie, Sofie Ashford, Antony Attwood, Joana Batista, Heleen Bouman, Frances Burden, Fizzah A Choudry, Laura Clarke, Paul Flicek, Stephen F Garner, Matthias Haimel, Carly Kempster, Vasileios Ladopoulos, An-Sofie Lenaerts, Paulina M Materek, Harriet McKinney, Stuart Meacham, Daniel Mead, Magdolna Nagy, Christopher J Penkett, Augusto Rendon, Denis Seyres, Benjamin Sun, Salih Tuna, Marie-Elise van der Weide, Steven W Wingett, Joost H Martens, Oliver Stegle, Sylvia Richardson, Ludovic Vallier, David J Roberts, Kathleen Freson, Lorenz Wernisch, Hendrik G Stunnenberg, John Danesh, Peter Fraser, Nicole Soranzo, Adam S Butterworth, Johan W Heemskerk, Ernest Turro, Mikhail Spivakov, Willem H Ouwehand, William J Astle, Kate Downes, Myrto Kostadima, Mattia Frontini
Linking non-coding genetic variants associated with the risk of diseases or disease-relevant traits to target genes is a crucial step to realize GWAS potential in the introduction of precision medicine. Here we set out to determine the mechanisms underpinning variant association with platelet quantitative traits using cell type-matched epigenomic data and promoter long-range interactions. We identify potential regulatory functions for 423 of 565 (75%) non-coding variants associated with platelet traits and we demonstrate, through ex vivo and proof of principle genome editing validation, that variants in super enhancers play an important role in controlling archetypical platelet functions...
July 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/28650485/neuroblastoma-is-composed-of-two-super-enhancer-associated-differentiation-states
#11
Tim van Groningen, Jan Koster, Linda J Valentijn, Danny A Zwijnenburg, Nurdan Akogul, Nancy E Hasselt, Marloes Broekmans, Franciska Haneveld, Natalia E Nowakowska, Johannes Bras, Carel J M van Noesel, Aldo Jongejan, Antoine H van Kampen, Linda Koster, Frank Baas, Lianne van Dijk-Kerkhoven, Margriet Huizer-Smit, Maria C Lecca, Alvin Chan, Arjan Lakeman, Piet Molenaar, Richard Volckmann, Ellen M Westerhout, Mohamed Hamdi, Peter G van Sluis, Marli E Ebus, Jan J Molenaar, Godelieve A Tytgat, Bart A Westerman, Johan van Nes, Rogier Versteeg
Neuroblastoma and other pediatric tumors show a paucity of gene mutations, which has sparked an interest in their epigenetic regulation. Several tumor types include phenotypically divergent cells, resembling cells from different lineage development stages. It has been proposed that super-enhancer-associated transcription factor (TF) networks underlie lineage identity, but the role of these enhancers in intratumoral heterogeneity is unknown. Here we show that most neuroblastomas include two types of tumor cells with divergent gene expression profiles...
August 2017: Nature Genetics
https://www.readbyqxmd.com/read/28637928/the-long-noncoding-rna-wisper-controls-cardiac-fibrosis-and-remodeling
#12
Rudi Micheletti, Isabelle Plaisance, Brian J Abraham, Alexandre Sarre, Ching-Chia Ting, Michael Alexanian, Daniel Maric, Damien Maison, Mohamed Nemir, Richard A Young, Blanche Schroen, Arantxa González, Samir Ounzain, Thierry Pedrazzini
Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of cardiac development and disease. However, our understanding of the importance of these molecules in cardiac fibrosis is limited. Using an integrated genomic screen, we identified Wisper (Wisp2 super-enhancer-associated RNA) as a cardiac fibroblast-enriched lncRNA that regulates cardiac fibrosis after injury. Wisper expression was correlated with cardiac fibrosis both in a murine model of myocardial infarction (MI) and in heart tissue from human patients suffering from aortic stenosis...
June 21, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28636939/the-super-enhancer-derived-alncrna-ec7-bloodlinc-potentiates-red-blood-cell-development-in%C3%A2-trans
#13
Juan R Alvarez-Dominguez, Marko Knoll, Austin A Gromatzky, Harvey F Lodish
Enhancer-derived RNAs are thought to act locally by contributing to their parent enhancer function. Whether large domains of clustered enhancers (super-enhancers) also produce cis-acting RNAs, however, remains unclear. Unlike typical enhancers, super-enhancers form large spans of robustly transcribed chromatin, amassing capped and polyadenylated RNAs that are sufficiently abundant to sustain trans functions. Here, we show that one such RNA, alncRNA-EC7/Bloodlinc, is transcribed from a super-enhancer of the erythroid membrane transporter SLC4A1/BAND3 but diffuses beyond this site...
June 20, 2017: Cell Reports
https://www.readbyqxmd.com/read/28601576/real-time-monitoring-of-microdistribution-of-antibody-photon-absorber-conjugates-during-photoimmunotherapy-in-vivo
#14
Qinggong Tang, Tadanobu Nagaya, Yi Liu, Jonathan Lin, Kazuhide Sato, Hisataka Kobayashi, Yu Chen
Photoimmunotherapy (PIT) is an emerging low side effect cancer therapy based on a monoclonal antibody (mAb) conjugated with a near-infrared (NIR) phthalocyanine dye IRDye 700DX. IR700 is fluorescent, can be used as an imaging agent, and also is phototoxic. It induces rapid cell death after exposure to NIR light. PIT induces highly selective cancer cell death, while leaving most of tumor blood vessels unharmed, leading to an effect called super-enhanced permeability and retention (SUPR). SUPR significantly improves the effectiveness of the anticancer drug...
June 8, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28583252/mice-deficient-of-myc-super-enhancer-region-reveal-differential-control-mechanism-between-normal-and-pathological-growth
#15
Kashyap Dave, Inderpreet Sur, Jian Yan, Jilin Zhang, Eevi Kaasinen, Fan Zhong, Leander Blaas, Xiaoze Li, Shabnam Kharazi, Charlotte Gustafsson, Ayla De Paepe, Robert Månsson, Jussi Taipale
The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50% to 80% decrease in Myc expression in multiple tissues. The mice are viable and show no overt phenotype...
June 6, 2017: ELife
https://www.readbyqxmd.com/read/28576751/targeting-of-super-enhancers-and-mutant-braf-can-suppress-growth-of-braf-mutant-colon-cancer-cells-via-repression-of-mapk-signaling-pathway
#16
Yoshiaki Nakamura, Naoko Hattori, Naoko Iida, Satoshi Yamashita, Akiko Mori, Kana Kimura, Takayuki Yoshino, Toshikazu Ushijima
Bromodomain and extra-terminal (BET) inhibitors suppress super-enhancers and show cytotoxicity against multiple types of tumors. However, early clinical trials with BET inhibitors showed severe hematopoietic toxicities, highlighting the need for sensitive tumors and rational combination strategies to enhance their therapeutic potential. Here, we identified colon cancer-specific super-enhancers that were associated with multiple oncogenic pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway...
August 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28575289/myod-and-foxo3-mediated-hotspot-interaction-orchestrates-super-enhancer-activity-during-myogenic-differentiation
#17
Xianlu L Peng, Karl K So, Liangqiang He, Yu Zhao, Jiajian Zhou, Yuying Li, Mingze Yao, Bo Xu, Suyang Zhang, Hongjie Yao, Ping Hu, Hao Sun, Huating Wang
Super-enhancers (SEs) are cis-regulatory elements enriching lineage specific key transcription factors (TFs) to form hotspots. A paucity of identification and functional dissection promoted us to investigate SEs during myoblast differentiation. ChIP-seq analysis of histone marks leads to the uncovering of SEs which remodel progressively during the course of differentiation. Further analyses of TF ChIP-seq enable the definition of SE hotspots co-bound by the master TF, MyoD and other TFs, among which we perform in-depth dissection for MyoD/FoxO3 interaction in driving the hotspots formation and SE activation...
June 1, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28572168/preclinical-efficacy-and-molecular-mechanism-of-targeting-cdk7-dependent-transcriptional-addiction-in-ovarian-cancer
#18
Zhenfeng Zhang, Huixin Peng, Xiaojie Wang, Xia Yin, Pengfei Ma, Ying Jing, Mei-Chun Cai, Jin Liu, Meiying Zhang, Shengzhe Zhang, Kaixuan Shi, Wei-Qiang Gao, Wen Di, Guanglei Zhuang
Ovarian cancer remains a significant cause of gynecological cancer mortality and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential anti-tumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identified THZ1, a recently developed covalent CDK7 inhibitor, as a new transcription-targeting compound that exerted broad cytotoxicity against ovarian tumors...
June 1, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28530713/bach2-immunodeficiency-illustrates-an-association-between-super-enhancers-and-haploinsufficiency
#19
Behdad Afzali, Juha Grönholm, Jana Vandrovcova, Charlotte O'Brien, Hong-Wei Sun, Ine Vanderleyden, Fred P Davis, Ahmad Khoder, Yu Zhang, Ahmed N Hegazy, Alejandro V Villarino, Ira W Palmer, Joshua Kaufman, Norman R Watts, Majid Kazemian, Olena Kamenyeva, Julia Keith, Anwar Sayed, Dalia Kasperaviciute, Michael Mueller, Jason D Hughes, Ivan J Fuss, Mohammed F Sadiyah, Kim Montgomery-Recht, Joshua McElwee, Nicholas P Restifo, Warren Strober, Michelle A Linterman, Paul T Wingfield, Holm H Uhlig, Rahul Roychoudhuri, Timothy J Aitman, Peter Kelleher, Michael J Lenardo, John J O'Shea, Nichola Cooper, Arian D J Laurence
The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency...
July 2017: Nature Immunology
https://www.readbyqxmd.com/read/28526829/super-enhancers-and-broad-h3k4me3-domains-form-complex-gene-regulatory-circuits-involving-chromatin-interactions
#20
Fan Cao, Yiwen Fang, Hong Kee Tan, Yufen Goh, Jocelyn Yeen Hui Choy, Bryan Thean Howe Koh, Jiong Hao Tan, Nicolas Bertin, Aroul Ramadass, Ewan Hunter, Jayne Green, Matthew Salter, Alexandre Akoulitchev, Wilson Wang, Wee Joo Chng, Daniel G Tenen, Melissa J Fullwood
Stretched histone regions, such as super-enhancers and broad H3K4me3 domains, are associated with maintenance of cell identity and cancer. We connected super-enhancers and broad H3K4me3 domains in the K562 chronic myelogenous leukemia cell line as well as the MCF-7 breast cancer cell line with chromatin interactions. Super-enhancers and broad H3K4me3 domains showed higher association with chromatin interactions than their typical counterparts. Interestingly, we identified a subset of super-enhancers that overlap with broad H3K4me3 domains and show high association with cancer-associated genes including tumor suppressor genes...
May 19, 2017: Scientific Reports
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