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Super enhancer transcription

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https://www.readbyqxmd.com/read/27923061/comparative-transcriptomic-and-epigenomic-analyses-reveal-new-regulators-of-murine-brown-adipogenesis
#1
Reinhard Brunmeir, Jingyi Wu, Xu Peng, Sun-Yee Kim, Sofi G Julien, Qiongyi Zhang, Wei Xie, Feng Xu
Increasing energy expenditure through brown adipocyte recruitment is a promising approach to combat obesity. We report here the comprehensive profiling of the epigenome and transcriptome throughout the lineage commitment and differentiation of C3H10T1/2 mesenchymal stem cell line into brown adipocytes. Through direct comparison to datasets from differentiating white adipocytes, we systematically identify stage- and lineage-specific coding genes, lncRNAs and microRNAs. Utilizing chromatin state maps, we also define stage- and lineage-specific enhancers, including super-enhancers, and their associated transcription factor binding motifs and genes...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27911843/impact-of-the-gut-microbiota-on-enhancer-accessibility-in-gut-intraepithelial-lymphocytes
#2
Nicholas P Semenkovich, Joseph D Planer, Philip P Ahern, Nicholas W Griffin, Charles Y Lin, Jeffrey I Gordon
The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to define chromatin accessibility in predicted enhancer regions of intestinal αβ(+) and γδ(+) intraepithelial lymphocytes purified from germ-free mice, their conventionally raised (CONV-R) counterparts, and mice reared germ free and then colonized with CONV-R gut microbiota at the end of the suckling-weaning transition...
December 1, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27895109/enhancers-and-super-enhancers-have-an-equivalent-regulatory-role-in-embryonic-stem-cells-through-regulation-of-single-or-multiple-genes
#3
Sakthi D Moorthy, Scott Davidson, Virlana M Shchuka, Gurdeep Singh, Nakisa Malek-Gilani, Lida Langroudi, Alexandre Martchenko, Vincent So, Neil N Macpherson, Jennifer A Mitchell
Transcriptional enhancers are critical for maintaining cell type-specific gene expression and driving cell fate changes during development. Highly transcribed genes are often associated with a cluster of individual enhancers such as those found in locus control regions. Recently these have been termed stretch enhancers or super-enhancers, which have been predicted to regulate critical cell identity genes. We employed a CRISPR/Cas9-mediated deletion approach to study the function of several enhancer clusters (ECs) and isolated enhancers in mouse embryonic stem (ES) cells...
November 28, 2016: Genome Research
https://www.readbyqxmd.com/read/27886174/5-hydroxymethylcytosine-localizes-to-enhancer-elements-and-is-associated-with-survival-in-glioblastoma-patients
#4
Kevin C Johnson, E Andres Houseman, Jessica E King, Katharine M von Herrmann, Camilo E Fadul, Brock C Christensen
Glioblastomas exhibit widespread molecular alterations including a highly distorted epigenome. Here, we resolve genome-wide 5-methylcytosine and 5-hydroxymethylcytosine in glioblastoma through parallel processing of DNA with bisulfite and oxidative bisulfite treatments. We apply a statistical algorithm to estimate 5-methylcytosine, 5-hydroxymethylcytosine and unmethylated proportions from methylation array data. We show that 5-hydroxymethylcytosine is depleted in glioblastoma compared with prefrontal cortex tissue...
November 25, 2016: Nature Communications
https://www.readbyqxmd.com/read/27864512/epstein-barr-virus-super-enhancer-ernas-are-essential-for-myc-oncogene-expression-and-lymphoblast-proliferation
#5
Jun Liang, Hufeng Zhou, Catherine Gerdt, Min Tan, Tyler Colson, Kenneth M Kaye, Elliott Kieff, Bo Zhao
Epstein-Barr virus (EBV) super-enhancers (ESEs) are essential for lymphoblastoid cell (LCL) growth and survival. Reanalyses of LCL global run-on sequencing (Gro-seq) data found abundant enhancer RNAs (eRNAs) being transcribed at ESEs. Inactivation of ESE components, EBV nuclear antigen 2 (EBNA2) and bromodomain-containing protein 4 (BRD4), significantly decreased eRNAs at ESEs -428 and -525 kb upstream of the MYC oncogene transcription start site (TSS). shRNA knockdown of the MYC -428 and -525 ESE eRNA caused LCL growth arrest and reduced cell growth...
November 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27846392/a-druggable-tcf4-and-brd4-dependent-transcriptional-network-sustains-malignancy-in-blastic-plasmacytoid-dendritic-cell-neoplasm
#6
Michele Ceribelli, Zhiying Esther Hou, Priscilla N Kelly, Da Wei Huang, George Wright, Karthik Ganapathi, Moses O Evbuomwan, Stefania Pittaluga, Arthur L Shaffer, Guido Marcucci, Stephen J Forman, Wenming Xiao, Rajarshi Guha, Xiaohu Zhang, Marc Ferrer, Laurence Chaperot, Joel Plumas, Elaine S Jaffe, Craig J Thomas, Boris Reizis, Louis M Staudt
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive and largely incurable hematologic malignancy originating from plasmacytoid dendritic cells (pDCs). Using RNAi screening, we identified the E-box transcription factor TCF4 as a master regulator of the BPDCN oncogenic program. TCF4 served as a faithful diagnostic marker of BPDCN, and its downregulation caused the loss of the BPDCN-specific gene expression program and apoptosis. High-throughput drug screening revealed that bromodomain and extra-terminal domain inhibitors (BETis) induced BPDCN apoptosis, which was attributable to disruption of a BPDCN-specific transcriptional network controlled by TCF4-dependent super-enhancers...
November 14, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27783597/transcription-of-the-non-coding-rna-upperhand-controls-hand2-expression-and-heart-development
#7
Kelly M Anderson, Douglas M Anderson, John R McAnally, John M Shelton, Rhonda Bassel-Duby, Eric N Olson
HAND2 is an ancestral regulator of heart development and one of four transcription factors that control the reprogramming of fibroblasts into cardiomyocytes. Deletion of Hand2 in mice results in right ventricle hypoplasia and embryonic lethality. Hand2 expression is tightly regulated by upstream enhancers that reside within a super-enhancer delineated by histone H3 acetyl Lys27 (H3K27ac) modifications. Here we show that transcription of a Hand2-associated long non-coding RNA, which we named upperhand (Uph), is required to maintain the super-enhancer signature and elongation of RNA polymerase II through the Hand2 enhancer locus...
October 26, 2016: Nature
https://www.readbyqxmd.com/read/27754335/anthocyanin-accumulation-in-muscadine-berry-skins-is-influenced-by-the-expression-of-the-myb-transcription-factors-myba1-and-mybcs1
#8
Lillian Oglesby, Anthony Ananga, James Obuya, Joel Ochieng, Ernst Cebert, Violeta Tsolova
The skin color of grape berry is very important in the wine industry. The red color results from the synthesis and accumulation of anthocyanins, which is regulated by transcription factors belonging to the MYB family. The transcription factors that activate the anthocyanin biosynthetic genes have been isolated in model plants. However, the genetic basis of color variation is species-specific and its understanding is relevant in many crop species. This study reports the isolation of MybA1, and MYBCS-1 genes from muscadine grapes for the first time...
October 12, 2016: Antioxidants (Basel, Switzerland)
https://www.readbyqxmd.com/read/27707886/exploitation-of-castration-resistant-prostate-cancer-transcription-factor-dependencies-by-the-novel-bet-inhibitor-abbv-075
#9
Emily J Faivre, Denise Wilcox, Xiaoyu Lin, Paul Hessler, Maricel Torrent, Wei He, Tamar Uziel, Daniel H Albert, Keith McDaniel, Warren Kati, Yu Shen
: Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/super-enhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the Androgen Receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075...
October 5, 2016: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27681417/super-enhancers-at-the-nanog-locus-differentially-regulate-neighboring-pluripotency-associated-genes
#10
Steven Blinka, Michael H Reimer, Kirthi Pulakanti, Sridhar Rao
Super-enhancers are tissue-specific cis-regulatory elements that drive expression of genes associated with cell identity and malignancy. A cardinal feature of super-enhancers is that they are transcribed to produce enhancer-derived RNAs (eRNAs). It remains unclear whether super-enhancers robustly activate genes in situ and whether their functions are attributable to eRNAs or the DNA element. CRISPR/Cas9 was used to systematically delete three discrete super-enhancers at the Nanog locus in embryonic stem cells, revealing functional differences in Nanog transcriptional regulation...
September 27, 2016: Cell Reports
https://www.readbyqxmd.com/read/27677335/epigenomic-profiling-of-primary-gastric-adenocarcinoma-reveals-super-enhancer-heterogeneity
#11
Wen Fong Ooi, Manjie Xing, Chang Xu, Xiaosai Yao, Muhammad Khairul Ramlee, Mei Chee Lim, Fan Cao, Kevin Lim, Deepak Babu, Lai-Fong Poon, Joyce Lin Suling, Aditi Qamra, Astrid Irwanto, James Qu Zhengzhong, Tannistha Nandi, Ai Ping Lee-Lim, Yang Sun Chan, Su Ting Tay, Ming Hui Lee, James O J Davies, Wai Keong Wong, Khee Chee Soo, Weng Hoong Chan, Hock Soo Ong, Pierce Chow, Chow Yin Wong, Sun Young Rha, Jianjun Liu, Axel M Hillmer, Jim R Hughes, Steve Rozen, Bin Tean Teh, Melissa Jane Fullwood, Shang Li, Patrick Tan
Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments...
September 28, 2016: Nature Communications
https://www.readbyqxmd.com/read/27643537/modeling-disease-risk-through-analysis-of-physical-interactions-between-genetic-variants-within-chromatin-regulatory-circuitry
#12
Olivia Corradin, Andrea J Cohen, Jennifer M Luppino, Ian M Bayles, Fredrick R Schumacher, Peter C Scacheri
SNPs associated with disease susceptibility often reside in enhancer clusters, or super-enhancers. Constituents of these enhancer clusters cooperate to regulate target genes and often extend beyond the linkage disequilibrium (LD) blocks containing risk SNPs identified in genome-wide association studies (GWAS). We identified 'outside variants', defined as SNPs in weak LD with GWAS risk SNPs that physically interact with risk SNPs as part of a target gene's regulatory circuitry. These outside variants further explain variation in target gene expression beyond that explained by GWAS-associated SNPs...
November 2016: Nature Genetics
https://www.readbyqxmd.com/read/27633377/genome-wide-identification-and-characterisation-of-hot-regions-in-the-human-genome
#13
Hao Li, Feng Liu, Chao Ren, Xiaochen Bo, Wenjie Shu
BACKGROUND: HOT (high-occupancy target) regions, which are bound by a surprisingly large number of transcription factors, are considered to be among the most intriguing findings of recent years. An improved understanding of the roles that HOT regions play in biology would be afforded by knowing the constellation of factors that constitute these domains and by identifying HOT regions across the spectrum of human cell types. RESULTS: We characterised and validated HOT regions in embryonic stem cells (ESCs) and produced a catalogue of HOT regions in a broad range of human cell types...
September 15, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27624132/tandemly-integrated-hpv16-can-form-a-brd4-dependent-super-enhancer-like-element-that-drives-transcription-of-viral-oncogenes
#14
Katharine E Dooley, Alix Warburton, Alison A McBride
UNLABELLED: In cancer cells associated with human papillomavirus (HPV) infections, the viral genome is very often found integrated into the cellular genome. The viral oncogenes E6 and E7 are transcribed from the viral promoter, and integration events that alter transcriptional regulation of this promoter contribute to carcinogenic progression. In this study, we detected highly enriched binding of the super-enhancer markers Brd4, MED1, and H3K27ac, visible as a prominent nuclear focus by immunofluorescence, at the tandemly integrated copies of HPV16 in cells of the cervical neoplasia cell line W12 subclone 20861...
2016: MBio
https://www.readbyqxmd.com/read/27620872/genome-wide-repression-of-erna-and-target-gene-loci-by-the-etv6-runx1-fusion-in-acute-leukemia
#15
Susanna Teppo, Saara Laukkanen, Thomas Liuksiala, Jessica Nordlund, Mikko Oittinen, Kaisa Teittinen, Toni Grönroos, Pascal St-Onge, Daniel Sinnett, Ann-Christine Syvänen, Matti Nykter, Keijo Viiri, Merja Heinäniemi, Olli Lohi
Approximately 20%-25% of childhood acute lymphoblastic leukemias carry the ETV6-RUNX1 (E/R) fusion gene, a fusion of two central hematopoietic transcription factors, ETV6 (TEL) and RUNX1 (AML1). Despite its prevalence, the exact genomic targets of E/R have remained elusive. We evaluated gene loci and enhancers targeted by E/R genome-wide in precursor B acute leukemia cells using global run-on sequencing (GRO-seq). We show that expression of the E/R fusion leads to widespread repression of RUNX1 motif-containing enhancers at its target gene loci...
November 2016: Genome Research
https://www.readbyqxmd.com/read/27604143/nsd2-contributes-to-oncogenic-ras-driven-transcription-in-lung-cancer-cells-through-long-range-epigenetic-activation
#16
Verónica García-Carpizo, Jacinto Sarmentero, Bomie Han, Osvaldo Graña, Sergio Ruiz-Llorente, David G Pisano, Manuel Serrano, Harold B Brooks, Robert M Campbell, Maria J Barrero
The histone methyltransferase NSD2/WHSC1/MMSET is overexpressed in a number of solid tumors but its contribution to the biology of these tumors is not well understood. Here, we describe that NSD2 contributes to the proliferation of a subset of lung cancer cell lines by supporting oncogenic RAS transcriptional responses. NSD2 knock down combined with MEK or BRD4 inhibitors causes co-operative inhibitory responses on cell growth. However, while MEK and BRD4 inhibitors converge in the downregulation of genes associated with cancer-acquired super-enhancers, NSD2 inhibition affects the expression of clusters of genes embedded in megabase-scale regions marked with H3K36me2 and that contribute to the RAS transcription program...
September 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27579716/remodeling-super-enhancers-and-oncogenic-transcription
#17
Li Wang, Guang Hu
No abstract text is available yet for this article.
August 11, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27571479/covalent-targeting-of-remote-cysteine-residues-to-develop-cdk12-and-cdk13-inhibitors
#18
Tinghu Zhang, Nicholas Kwiatkowski, Calla M Olson, Sarah E Dixon-Clarke, Brian J Abraham, Ann K Greifenberg, Scott B Ficarro, Jonathan M Elkins, Yanke Liang, Nancy M Hannett, Theresa Manz, Mingfeng Hao, Bartlomiej Bartkowiak, Arno L Greenleaf, Jarrod A Marto, Matthias Geyer, Alex N Bullock, Richard A Young, Nathanael S Gray
Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12-cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain...
October 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27533466/adenoid-cystic-carcinoma-emerging-role-of-translocations-and-gene-fusions
#19
Piotr T Wysocki, Evgeny Izumchenko, Juliet Meir, Patrick K Ha, David Sidransky, Mariana Brait
Adenoid cystic carcinoma (ACC), the second most common salivary gland malignancy, is notorious for poor prognosis, which reflects the propensity of ACC to progress to clinically advanced metastatic disease. Due to high long-term mortality and lack of effective systemic treatment, the slow-growing but aggressive ACC poses a particular challenge in head and neck oncology. Despite the advancements in cancer genomics, up until recently relatively few genetic alterations critical to the ACC development have been recognized...
August 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27524613/genetic-predisposition-to-chronic-lymphocytic-leukemia-is-mediated-by-a-bmf-super-enhancer-polymorphism
#20
Radhika Kandaswamy, Georgina P Sava, Helen E Speedy, Sílvia Beà, José I Martín-Subero, James B Studd, Gabriele Migliorini, Philip J Law, Xose S Puente, David Martín-García, Itziar Salaverria, Jesús Gutiérrez-Abril, Carlos López-Otín, Daniel Catovsky, James M Allan, Elías Campo, Richard S Houlston
Chronic lymphocytic leukemia (CLL) is an adult B cell malignancy. Genome-wide association studies show that variation at 15q15.1 influences CLL risk. We deciphered the causal variant at 15q15.1 and the mechanism by which it influences tumorigenesis. We imputed all possible genotypes across the locus and then mapped highly associated SNPs to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding. SNP rs539846 C>A, the most highly associated variant (p = 1.42 × 10(-13), odds ratio = 1...
August 23, 2016: Cell Reports
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