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https://www.readbyqxmd.com/read/29454790/increased-expression-of-the-long-non-coding-rna-linc01503-regulated-by-tp63-in-squamous-cell-carcinoma-and-effects-on-oncogenic-activities-of-cancer-cell-lines
#1
Jian-Jun Xie, Yan-Yi Jiang, Yuan Jiang, Chun-Quan Li, Lim-Mei Chee, Omer An, Anand Mayakonda, Ling-Wen Ding, Lin Long, Chun Sun, Le-Hang Lin, Li Chen, Jian-Yi Wu, Zhi-Yong Wu, Qi Cao, Wang-Kai Fang, Wei Yang, Stephen J Meltzer, Henry Yang, Melissa Fullwood, Li-Yan Xu, En-Min Li, De-Chen Lin, H Phillip Koeffler
BACKGROUND & AIMS: Long non-coding RNAs (lncRNAs) are expressed in tissue-specific pattern, but it is not clear how these are regulated. We aimed to identify squamous cell carcinoma (SCC)-specific lncRNAs and investigate mechanisms that control their expression and function. METHODS: We studied expression patterns and functions of 4 SCC-specific lncRNAs. We obtained 113 esophageal SCC (ESCC) and matched non-tumor esophageal tissues from a hospital in Shantou City, China, and performed quantitative reverse transcription PCR assays to measure expression levels of LINC01503...
February 15, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29452225/seminars-in-cell-and-developmental-biology-human-dendritic-cell-immunodeficiencies
#2
REVIEW
Venetia Bigley, Urszula Cytlak, Matthew Collin
The critical functions of dendritic cells (DCs) in immunity and tolerance have been demonstrated in many animal models but their non-redundant roles in humans are more difficult to probe. Human primary immunodeficiency (PID), resulting from single gene mutations, may result in DC deficiency or dysfunction. This relatively recent recognition illuminates the in vivo role of human DCs and the pathophysiology of the associated clinical syndromes. In this review, the development and function of DCs as established in murine models and human in vitro systems, is discussed...
February 13, 2018: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/29444854/bet-bromodomain-proteins-regulate-enhancer-function-during-adipogenesis
#3
Jonathan D Brown, Zachary B Feldman, Sean P Doherty, Jaime M Reyes, Peter B Rahl, Charles Y Lin, Quanhu Sheng, Qiong Duan, Alexander J Federation, Andrew L Kung, Saptarsi M Haldar, Richard A Young, Jorge Plutzky, James E Bradner
Developmental transitions are guided by master regulatory transcription factors. During adipogenesis, a transcriptional cascade culminates in the expression of PPARγ and C/EBPα, which orchestrate activation of the adipocyte gene expression program. However, the coactivators controlling PPARγ and C/EBPα expression are less well characterized. Here, we show the bromodomain-containing protein, BRD4, regulates transcription of PPARγ and C/EBPα. Analysis of BRD4 chromatin occupancy reveals that induction of adipogenesis in 3T3L1 fibroblasts provokes dynamic redistribution of BRD4 to de novo super-enhancers proximal to genes controlling adipocyte differentiation...
February 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29416716/robust-diagnosis-of-ewing-sarcoma-by-immunohistochemical-detection-of-super-enhancer-driven-ewsr1-ets-targets
#4
Michaela C Baldauf, Martin F Orth, Marlene Dallmayer, Aruna Marchetto, Julia S Gerke, Rebeca Alba Rubio, Merve M Kiran, Julian Musa, Maximilian M L Knott, Shunya Ohmura, Jing Li, Nusret Akpolat, Ayse N Akatli, Özlem Özen, Uta Dirksen, Wolfgang Hartmann, Enrique de Alava, Daniel Baumhoer, Giuseppina Sannino, Thomas Kirchner, Thomas G P Grünewald
Ewing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4-, BCOR-CCNB3-, EWSR1-NFATc2-, and EWSR1-ETS-translocated sarcomas are distinct entities, and revealed that ATP1A1, BCL11B, and GLG1 constitute specific markers for Ewing sarcoma...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416042/stratification-of-tad-boundaries-reveals-preferential-insulation-of-super-enhancers-by-strong-boundaries
#5
Yixiao Gong, Charalampos Lazaris, Theodore Sakellaropoulos, Aurelie Lozano, Prabhanjan Kambadur, Panagiotis Ntziachristos, Iannis Aifantis, Aristotelis Tsirigos
The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score...
February 7, 2018: Nature Communications
https://www.readbyqxmd.com/read/29415456/bet-family-protein-brd4-an-emerging-actor-in-nf%C3%AE%C2%BAb-signaling-in-inflammation-and-cancer
#6
REVIEW
Azadeh Hajmirza, Anouk Emadali, Arnaud Gauthier, Olivier Casasnovas, Rémy Gressin, Mary B Callanan
NFκB (Nuclear Factor- κ -light-chain-enhancer of activated B cells) signaling elicits global transcriptional changes by activating cognate promoters and through genome-wide remodeling of cognate regulatory elements called "super enhancers". BET (Bromodomain and Extra-Terminal domain) protein family inhibitor studies have implicated BET protein member BRD4 and possibly other BET proteins in NFκB-dependent promoter and super-enhancer modulation. Members of the BET protein family are known to bind acetylated chromatin to facilitate access by transcriptional regulators to chromatin, as well as to assist the activity of transcription elongation complexes via CDK9/pTEFb...
February 6, 2018: Biomedicines
https://www.readbyqxmd.com/read/29408204/high-mitf-expression-is-associated-with-super-enhancers-and-suppressed-by-cdk7-inhibition-in-melanoma
#7
Philip Eliades, Brian J Abraham, Zhenyu Ji, David M Miller, Camilla L Christensen, Nicholas Kwiatkowski, Raj Kumar, Ching Ni Njauw, Michael Taylor, Benchun Miao, Tinghu Zhang, Kwok-Kin Wong, Nathanael S Gray, Richard A Young, Hensin Tsao
Cutaneous melanoma is an aggressive tumor which accounts for most of the skin cancer deaths. Among the physiological barriers against therapeutic success is a strong survival program driven by genes that specify melanocyte identity such as MITF - a phenomenon known in melanoma biology as "lineage dependency." MITF overexpression is occasionally explained by gene amplification, but here we demonstrate that "super-enhancers" are also important determinants of MITF overexpression in some melanoma cell lines and tumors...
February 2, 2018: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/29394393/decoding-the-dynamic-dna-methylation-and-hydroxymethylation-landscapes-in-endodermal-lineage-intermediates-during-pancreatic-differentiation-of-hesc
#8
Jia Li, Xinwei Wu, Yubin Zhou, Minjung Lee, Lei Guo, Wei Han, William Mo, Wen-Ming Cao, Deqiang Sun, Ruiyu Xie, Yun Huang
Dynamic changes in DNA methylation and demethylation reprogram transcriptional outputs to instruct lineage specification during development. Here, we applied an integrative epigenomic approach to unveil DNA (hydroxy)methylation dynamics representing major endodermal lineage intermediates during pancreatic differentiation of human embryonic stem cells (hESCs). We found that 5-hydroxymethylcytosine (5hmC) marks genomic regions to be demethylated in the descendent lineage, thus reshaping the DNA methylation landscapes during pancreatic lineage progression...
January 31, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29394256/the-natural-anti-tumor-compound-celastrol-targets-a-myb-c-ebp%C3%AE-p300-transcriptional-module-implicated-in-myeloid-gene-expression
#9
Anna Coulibaly, Astrid Haas, Simone Steinmann, Anke Jakobs, Thomas J Schmidt, Karl-Heinz Klempnauer
Myb is a key regulator of hematopoietic progenitor cell proliferation and differentiation and has emerged as a potential target for the treatment of acute leukemia. Using a myeloid cell line with a stably integrated Myb-inducible reporter gene as a screening tool we have previously identified Celastrol, a natural compound with anti-tumor activity, as a potent Myb inhibitor that disrupts the interaction of Myb with the co-activator p300. We showed that Celastrol inhibits the proliferation of acute myeloid leukemia (AML) cells and prolongs the survival of mice in an in vivo model of AML, demonstrating that targeting Myb with a small-molecule inhibitor is feasible and might have potential as a therapeutic approach against AML...
2018: PloS One
https://www.readbyqxmd.com/read/29385209/integrative-analysis-of-super-enhancer-snps-for-type-2-diabetes
#10
Weiping Sun, Sihong Yao, Jielong Tang, Shuai Liu, Juan Chen, Daqing Deng, Chunping Zeng
Clinical studies in type 2 diabetes (T2D) primarily focused on the single nucleotide polymorphisms (SNPs) located in protein-coding regions. Recently, the SNPs located in noncoding regions have also been recognized to play an important role in disease susceptibility. The super enhancer is a cluster of transcriptional enhancers located in noncoding regions. It plays a critical role in cell-type specific gene expression. However, the exact mechanism of the super enhancer SNPs for T2D remains unclear. In this study, we integrated genome-wide association studies (GWASs) and T2D cell/tissue-specific histone modification ChIP-seq data to identify T2D-associated SNPs in super enhancer, followed by comprehensive bioinformatics analyses to further explore the functional importance of these SNPs...
2018: PloS One
https://www.readbyqxmd.com/read/29379197/brd4-interacts-with-nipbl-and-brd4-is-mutated-in-a-cornelia-de-lange-like-syndrome
#11
Gabrielle Olley, Morad Ansari, Hemant Bengani, Graeme R Grimes, James Rhodes, Alex von Kriegsheim, Ana Blatnik, Fiona J Stewart, Emma Wakeling, Nicola Carroll, Alison Ross, Soo-Mi Park, Wendy A Bickmore, Madapura M Pradeepa, David R FitzPatrick
We found that the clinical phenotype associated with BRD4 haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression.
January 29, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29364907/hpv-integration-hijacks-and-multimerizes-a-cellular-enhancer-to-generate-a-viral-cellular-super-enhancer-that-drives-high-viral-oncogene-expression
#12
Alix Warburton, Catherine J Redmond, Katharine E Dooley, Haiqing Fu, Maura L Gillison, Keiko Akagi, David E Symer, Mirit I Aladjem, Alison A McBride
Integration of human papillomavirus (HPV) genomes into cellular chromatin is common in HPV-associated cancers. Integration is random, and each site is unique depending on how and where the virus integrates. We recently showed that tandemly integrated HPV16 could result in the formation of a super-enhancer-like element that drives transcription of the viral oncogenes. Here, we characterize the chromatin landscape and genomic architecture of this integration locus to elucidate the mechanisms that promoted de novo super-enhancer formation...
January 24, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29342133/a-myc-enhancer-cluster-regulates-normal-and-leukaemic-haematopoietic-stem-cell-hierarchies
#13
Carsten Bahr, Lisa von Paleske, Veli V Uslu, Silvia Remeseiro, Naoya Takayama, Stanley W Ng, Alex Murison, Katja Langenfeld, Massimo Petretich, Roberta Scognamiglio, Petra Zeisberger, Amelie S Benk, Ido Amit, Peter W Zandstra, Mathieu Lupien, John E Dick, Andreas Trumpp, François Spitz
The transcription factor Myc is essential for the regulation of haematopoietic stem cells and progenitors and has a critical function in haematopoietic malignancies. Here we show that an evolutionarily conserved region located 1.7 megabases downstream of the Myc gene that has previously been labelled as a 'super-enhancer' is essential for the regulation of Myc expression levels in both normal haematopoietic and leukaemic stem cell hierarchies in mice and humans. Deletion of this region in mice leads to a complete loss of Myc expression in haematopoietic stem cells and progenitors...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29339538/e6-protein-expressed-by-high-risk-hpv-activates-super-enhancers-of-the-egfr-and-c-met-oncogenes-by-destabilizing-the-histone-demethylase-kdm5c
#14
Xiaohua Chen, Jun Xian Loo, Xin Shi, Wenjun Xiong, Yong Guo, Haiqiang Ke, Mingkun Yang, Yanping Jiang, Siyu Xia, Min Zhao, Shan Zhong, ChunJiang He, Li Fu, Feng Li
The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events are poorly understood. Here we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner...
January 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29339447/guidance-of-super-enhancers-in-regulation-of-il-9-induction-and-airway-inflammation
#15
Xiang Xiao, Yihui Fan, Junhui Li, Xiaolong Zhang, Xiaohua Lou, Yaling Dou, Xiaomin Shi, Peixiang Lan, Yue Xiao, Laurie Minze, Xian Chang Li
Th9 cells are prominently featured in allergic lung inflammation, but the mechanism that regulates IL-9 induction in T helper cells remains poorly defined. Here we demonstrate that formation of super-enhancers (SEs) is critical in robust induction of IL-9 and that assembly of the Il9 SEs in Th cells requires OX40-triggered chromatin acetylation. Mechanistically, we found that OX40 costimulation induces RelB expression, which recruits the histone acetyltransferase p300 to the Il9 locus to catalyze H3K27 acetylation...
January 16, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29335803/contribution-of-transposable-elements-and-distal-enhancers-to-evolution-of-human-specific-features-of-interphase-chromatin-architecture-in-embryonic-stem-cells
#16
Gennadi V Glinsky
Transposable elements have made major evolutionary impacts on creation of primate-specific and human-specific genomic regulatory loci and species-specific genomic regulatory networks (GRNs). Molecular and genetic definitions of human-specific changes to GRNs contributing to development of unique to human phenotypes remain a highly significant challenge. Genome-wide proximity placement analysis of diverse families of human-specific genomic regulatory loci (HSGRL) identified topologically associating domains (TADs) that are significantly enriched for HSGRL and designated rapidly evolving in human TADs...
January 15, 2018: Chromosome Research
https://www.readbyqxmd.com/read/29321583/allele-specific-repression-of-sox2-through-the-long-non-coding-rna-sox2ot
#17
Tobias C Messemaker, Selina M van Leeuwen, Patrick R van den Berg, Anke E J 't Jong, Robert-Jan Palstra, Rob C Hoeben, Stefan Semrau, Harald M M Mikkers
The transcription factor Sox2 controls the fate of pluripotent stem cells and neural stem cells. This gatekeeper function requires well-regulated Sox2 levels. We postulated that Sox2 regulation is partially controlled by the Sox2 overlapping long non-coding RNA (lncRNA) gene Sox2ot. Here we show that the RNA levels of Sox2ot and Sox2 are inversely correlated during neural differentiation of mouse embryonic stem cells (ESCs). Through allele-specific enhanced transcription of Sox2ot in mouse Sox2eGFP knockin ESCs we demonstrate that increased Sox2ot transcriptional activity reduces Sox2 RNA levels in an allele-specific manner...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29320736/the-rna-polymerase-ii-factor-rpap1-is-critical-for-mediator-driven-transcription-and-cell-identity
#18
Cian J Lynch, Raquel Bernad, Isabel Calvo, Sandrina Nóbrega-Pereira, Sergio Ruiz, Nuria Ibarz, Ana Martinez-Val, Osvaldo Graña-Castro, Gonzalo Gómez-López, Eduardo Andrés-León, Vladimir Espinosa Angarica, Antonio Del Sol, Sagrario Ortega, Oscar Fernandez-Capetillo, Enrique Rojo, Javier Munoz, Manuel Serrano
The RNA polymerase II-associated protein 1 (RPAP1) is conserved across metazoa and required for stem cell differentiation in plants; however, very little is known about its mechanism of action or its role in mammalian cells. Here, we report that RPAP1 is essential for the expression of cell identity genes and for cell viability. Depletion of RPAP1 triggers cell de-differentiation, facilitates reprogramming toward pluripotency, and impairs differentiation. Mechanistically, we show that RPAP1 is essential for the interaction between RNA polymerase II (RNA Pol II) and Mediator, as well as for the recruitment of important regulators, such as the Mediator-specific RNA Pol II factor Gdown1 and the C-terminal domain (CTD) phosphatase RPAP2...
January 9, 2018: Cell Reports
https://www.readbyqxmd.com/read/29285248/super-enhancer-associated-rai14-is-a-new-potential-biomarker-in-lung-adenocarcinoma
#19
Chongze Yuan, Hong Hu, Muyu Kuang, Zongwei Chen, Xiaoting Tao, Shengjian Fang, Yihua Sun, Yawei Zhang, Haiquan Chen
Purpose: Tyrosine kinase inhibitors (TKIs) are widely used to treat lung adenocarcinoma patients with EGFR mutations or ALK-fusions. However, patients with wild-type genes or TKIs-resistant mutations lack effective therapeutic targets. Extensive studies reveal that super enhancer (SE), a large cis-regulatory element, is associated with key oncogenes in a variety of cancers. By comparing the effect of SE on lung adenocarcinoma cell lines with normal cell line, this work attempts to find new biomarkers and potential therapeutic targets for lung adenocarcinoma...
December 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/29258295/therapeutic-targeting-of-ependymoma-as-informed-by-oncogenic-enhancer-profiling
#20
Stephen C Mack, Kristian W Pajtler, Lukas Chavez, Konstantin Okonechnikov, Kelsey C Bertrand, Xiuxing Wang, Serap Erkek, Alexander Federation, Anne Song, Christine Lee, Xin Wang, Laura McDonald, James J Morrow, Alina Saiakhova, Patrick Sin-Chan, Qiulian Wu, Kulandaimanuvel Antony Michaelraj, Tyler E Miller, Christopher G Hubert, Marina Ryzhova, Livia Garzia, Laura Donovan, Stephen Dombrowski, Daniel C Factor, Betty Luu, Claudia L L Valentim, Ryan C Gimple, Andrew Morton, Leo Kim, Briana C Prager, John J Y Lee, Xiaochong Wu, Jennifer Zuccaro, Yuan Thompson, Borja L Holgado, Jüri Reimand, Susan Q Ke, Adam Tropper, Sisi Lai, Senthuran Vijayarajah, Sylvia Doan, Vaidehi Mahadev, Ana Fernandez Miñan, Susanne N Gröbner, Matthias Lienhard, Marc Zapatka, Zhiqin Huang, Kenneth D Aldape, Angel M Carcaboso, Peter J Houghton, Stephen T Keir, Till Milde, Hendrik Witt, Yan Li, Chao-Jun Li, Xiu-Wu Bian, David T W Jones, Ian Scott, Sheila K Singh, Annie Huang, Peter B Dirks, Eric Bouffet, James E Bradner, Vijay Ramaswamy, Nada Jabado, James T Rutka, Paul A Northcott, Mathieu Lupien, Peter Lichter, Andrey Korshunov, Peter C Scacheri, Stefan M Pfister, Marcel Kool, Michael D Taylor, Jeremy N Rich
Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy...
December 20, 2017: Nature
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