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Super enhancer transcription

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https://www.readbyqxmd.com/read/29648668/widespread-enhancer-activation-via-er%C3%AE-mediates-estrogen-response-in-vivo-during-uterine-development
#1
Wendy N Jefferson, H Karimi Kinyamu, Tianyuan Wang, Adam X Miranda, Elizabeth Padilla-Banks, Alisa A Suen, Carmen J Williams
Little is known regarding how steroid hormone exposures impact the epigenetic landscape in a living organism. Here, we took a global approach to understanding how exposure to the estrogenic chemical, diethylstilbestrol (DES), affects the neonatal mouse uterine epigenome. Integration of RNA- and ChIP-sequencing data demonstrated that ∼80% of DES-altered genes had higher H3K4me1/H3K27ac signal in close proximity. Active enhancers, of which ∼3% were super-enhancers, had a high density of estrogen receptor alpha (ERα) binding sites and were correlated with alterations in nearby gene expression...
April 10, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29644114/super-enhancer-inhibitors-suppress-myc-driven-transcriptional-amplification-and-tumor-progression-in-osteosarcoma
#2
Demeng Chen, Zhiqiang Zhao, Zixin Huang, Du-Chu Chen, Xin-Xing Zhu, Yi-Ze Wang, Ya-Wei Yan, Shaojun Tang, Subha Madhavan, Weiyi Ni, Zhan-Peng Huang, Wen Li, Weidong Ji, Huangxuan Shen, Shuibin Lin, Yi-Zhou Jiang
Osteosarcoma is the most common primary bone sarcoma that mostly occurs in young adults. The causes of osteosarcoma are heterogeneous and still not fully understood. Identification of novel, important oncogenic factors in osteosarcoma and development of better, effective therapeutic approaches are in urgent need for better treatment of osteosarcoma patients. In this study, we uncovered that the oncogene MYC is significantly upregulated in metastastic osteosarcoma samples. In addition, high MYC expression is associated with poor survival of osteosarcoma patients...
2018: Bone Research
https://www.readbyqxmd.com/read/29625024/a-common-type-2-diabetes-risk-variant-potentiates-activity-of-an-evolutionarily-conserved-islet-stretch-enhancer-and-increases-c2cd4a-and-c2cd4b-expression
#3
Ina Kycia, Brooke N Wolford, Jeroen R Huyghe, Christian Fuchsberger, Swarooparani Vadlamudi, Romy Kursawe, Ryan P Welch, Ricardo d'Oliveira Albanus, Asli Uyar, Shubham Khetan, Nathan Lawlor, Mohan Bolisetty, Anubhuti Mathur, Johanna Kuusisto, Markku Laakso, Duygu Ucar, Karen L Mohlke, Michael Boehnke, Francis S Collins, Stephen C J Parker, Michael L Stitzel
Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of effect, and elucidate plausible target genes. Fine-mapping and conditional analyses of proinsulin levels of 8,635 non-diabetic individuals from the METSIM study support a single association signal represented by a cluster of 16 strongly associated (p < 10-17 ) variants in high linkage disequilibrium (r2 > 0...
April 5, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29577113/stat1-is-required-for-suppression-of-type-17-immunity-during-influenza-and-bacterial-superinfection
#4
Benjamin Lee, Radha Gopal, Michelle L Manni, Kevin J McHugh, Sivanarayana Mandalapu, Keven M Robinson, John F Alcorn
Influenza is an annual, global health care concern. Secondary bacterial pneumonia is a severe complication associated with primary influenza virus infection, often resulting in critical morbidity and mortality. Our laboratory has identified influenza-induced suppression of anti-bacterial Type 17 immunity as a mechanism for enhanced susceptibility to bacterial super-infection. We have shown that influenza-induced type I interferon impairs Type 17 activation. STAT1 is a transcription factor involved in interferon signaling, shared by type I, II, and III interferon...
August 1, 2017: ImmunoHorizons
https://www.readbyqxmd.com/read/29552153/-in-silico-analysis-identifies-crisp3-as-a-potential-peripheral-blood-biomarker-for-multiple-myeloma-from-data-modeling-to-validation-with-rt-pcr
#5
Dong Leng, Ran Miao, Xiaoxi Huang, Ying Wang
Octamer-binding protein 2 (Oct2) binds to the ATGCAAAT octamer on the IgH enhancer and stimulates IgH expression in human multiple myeloma (MM). Cysteine-rich secreted protein 3 (CRISP3) possesses the ATGCAAAT sequence and thus is activated by Oct2 in mouse B cells, suggesting that CRISP3 may be activated in and be a potential biomarker for MM. The present study involved a meta-analysis of the gene expression profiling data of human MM peripheral blood. Significantly expressed genes were analyzed on merged super array microarray data and selected sample data with significantly expressed genes were additionally analyzed by principal component analysis and Bayesian probit regression...
April 2018: Oncology Letters
https://www.readbyqxmd.com/read/29528523/multiple-functional-variants-at-13q14-risk-locus-for-osteoporosis-regulate-rankl-expression-through-long-range-super-enhancer
#6
Dong-Li Zhu, Xiao-Feng Chen, Wei-Xin Hu, Shan-Shan Dong, Bing-Jie Lu, Yu Rong, Yi-Xiao Chen, Hao Chen, Hlaing Nwe Thynn, Nai-Ning Wang, Yan Guo, Tie-Lin Yang
RANKL is a key regulator involved in bone metabolism, and a drug target for osteoporosis. The clinical diagnosis and assessment of osteoporosis are mainly based on bone mineral density (BMD). Previous powerful genome-wide association studies (GWASs) have identified multiple intergenic single nucleotide polymorphisms (SNPs) located over 100 kb upstream of RANKL and 65 kb downstream of AKAP11 at 13q14.11 for osteoporosis. Whether these SNPs exert their roles on osteoporosis through RANKL is unknown. In this study, we conducted integrative analyses combining expression quantitative trait locus (eQTL), genomic chromatin interaction (Hi-C), epigenetic annotation and a series of functional assays...
March 12, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29519805/active-enhancer-and-chromatin-accessibility-landscapes-chart-the-regulatory-network-of-primary-multiple-myeloma
#7
Yi Jin, Kenian Chen, Ayla De Paepe, Eva Hellqvist, Aleksandra D Krstic, Lauren Metang, Charlotte Gustafsson, Richard E Davis, Yair M Levy, Rakesh Surapaneni, Ann Wallblom, Hareth Nahi, Robert Mansson, Yin C Lin
Multiple myeloma (MM) is an aggressive cancer that originates from antibody-secreting plasma cells. While genetically and transcriptionally well characterized, the aberrant gene regulatory networks that underpin this disease remain poorly understood. Here, we mapped regulatory elements, open chromatin and transcription factor footprints in primary MM cells. In comparison to normal antibody-secreting cells, MM cells displayed consistent changes in enhancer activity that are connected to super-enhancer (SE)-mediated deregulation of transcription factor (TF) genes...
March 8, 2018: Blood
https://www.readbyqxmd.com/read/29514091/long-range-enhancer-interactions-are-prevalent-in-mouse-embryonic-stem-cells-and-are-reorganized-upon-pluripotent-state-transition
#8
Clara Lopes Novo, Biola-Maria Javierre, Jonathan Cairns, Anne Segonds-Pichon, Steven W Wingett, Paula Freire-Pritchett, Mayra Furlan-Magaril, Stefan Schoenfelder, Peter Fraser, Peter J Rugg-Gunn
Transcriptional enhancers, including super-enhancers (SEs), form physical interactions with promoters to regulate cell-type-specific gene expression. SEs are characterized by high transcription factor occupancy and large domains of active chromatin, and they are commonly assigned to target promoters using computational predictions. How promoter-SE interactions change upon cell state transitions, and whether transcription factors maintain SE interactions, have not been reported. Here, we used promoter-capture Hi-C to identify promoters that interact with SEs in mouse embryonic stem cells (ESCs)...
March 6, 2018: Cell Reports
https://www.readbyqxmd.com/read/29511351/hpse-enhancer-rna-promotes-cancer-progression-through-driving-chromatin-looping-and-regulating-hnrnpu-p300-egr1-hpse-axis
#9
Wanju Jiao, Yajun Chen, Huajie Song, Dan Li, Hong Mei, Feng Yang, Erhu Fang, Xiaojing Wang, Kai Huang, Liduan Zheng, Qiangsong Tong
Recent studies reveal the emerging functions of enhancer RNAs (eRNAs) in gene expression. However, the roles of eRNAs in regulating the expression of heparanase (HPSE), an established endo-β-D-glucuronidase essential for cancer invasion and metastasis, still remain elusive. Herein, through comprehensive analysis of publically available FANTOM5 expression atlas and chromatin interaction dataset, we identified a super enhancer and its derived eRNA facilitating the HPSE expression (HPSE eRNA) in cancers. Gain-of-function and loss-of-function experiments indicated that HPSE eRNA facilitated the in vitro and in vivo tumorigenesis and aggressiveness of cancer cells...
March 7, 2018: Oncogene
https://www.readbyqxmd.com/read/29503092/yy1-positively-regulates-transcription-by-targeting-promoters-and-super-enhancers-through-the-baf-complex-in-embryonic-stem-cells
#10
Jia Wang, Xingui Wu, Chao Wei, Xin Huang, Qian Ma, Xiaona Huang, Francesco Faiola, Diana Guallar, Miguel Fidalgo, Tingyuan Huang, Di Peng, Li Chen, Haopeng Yu, Xingyu Li, Junyi Sun, Xinyi Liu, Xiaoxia Cai, Xiao Chen, Ling Wang, Jian Ren, Jianlong Wang, Junjun Ding
Yin Yang 1 (YY1) regulates early embryogenesis and adult tissue formation. However, the role of YY1 in stem cell regulation remains unclear. YY1 has a Polycomb group (PcG) protein-dependent role in mammalian cells. The PcG-independent functions of YY1 are also reported, although their underlying mechanism is still undefined. This paper reports the role of YY1 and BAF complex in the OCT4-mediated pluripotency network in mouse embryonic stem cells (mESCs). The interaction between YY1 and BAF complex promotes mESC proliferation and pluripotency...
April 10, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29498561/developmentally-linked-human-dna-hypermethylation-is-associated-with-down-modulation-repression-and-upregulation-of-transcription
#11
Carl Baribault, Kenneth C Ehrlich, V K Chaithanya Ponnaluri, Sriharsa Pradhan, Michelle Lacey, Melanie Ehrlich
DNA methylation can affect tissue-specific gene transcription in ways that are difficult to discern from studies focused on genome-wide analyses of differentially methylated regions (DMRs). To elucidate the variety of associations between differentiation-related DNA hypermethylation and transcription, we used available epigenomic and transcriptomic profiles from 38 human cell/tissue types to focus on such relationships in 94 genes linked to hypermethylated DMRs in myoblasts (Mb). For 19 of the genes, promoter-region hypermethylation in Mb (and often a few heterologous cell types) was associated with gene repression but, importantly, DNA hypermethylation was absent in many other repressed samples...
March 2, 2018: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/29491472/integrative-functional-analysis-of-super-enhancer-snps-for-coronary-artery-disease
#12
Juexiao Gong, Chuan Qiu, Dan Huang, Yiyan Zhang, Shengyong Yu, Chunping Zeng
Clinical research in coronary artery disease (CAD) primarily focused on genetic variants located in protein-coding regions. Recently, mutations fall within non-coding regions have been suggested to be essential to the pathogenesis of human complex disease. Super enhancer is a densely spaced cluster of transcriptional enhancers located in non-coding regions, which is critical for regulating cell-type specific gene expression. However, the underlying mechanism of the super enhancer single-nucleotide polymorphisms (SNPs) affecting the risk of CAD remains unclear...
February 28, 2018: Journal of Human Genetics
https://www.readbyqxmd.com/read/29491412/the-novel-bet-bromodomain-inhibitor-bi-894999-represses-super-enhancer-associated-transcription-and-synergizes-with-cdk9-inhibition-in-aml
#13
Daniel Gerlach, Ulrike Tontsch-Grunt, Anke Baum, Johannes Popow, Dirk Scharn, Marco H Hofmann, Harald Engelhardt, Onur Kaya, Janina Beck, Norbert Schweifer, Thomas Gerstberger, Johannes Zuber, Fabio Savarese, Norbert Kraut
Bromodomain and extra-terminal (BET) protein inhibitors have been reported as treatment options for acute myeloid leukemia (AML) in preclinical models and are currently being evaluated in clinical trials. This work presents a novel potent and selective BET inhibitor (BI 894999), which has recently entered clinical trials (NCT02516553). In preclinical studies, this compound is highly active in AML cell lines, primary patient samples, and xenografts. HEXIM1 is described as an excellent pharmacodynamic biomarker for target engagement in tumors as well as in blood...
March 1, 2018: Oncogene
https://www.readbyqxmd.com/read/29462945/luminal-lncrnas-regulation-by-er%C3%AE-controlled-enhancers-in-a-ligand-independent-manner-in-breast-cancer-cells
#14
Valentina Miano, Giulio Ferrero, Valentina Rosti, Eleonora Manitta, Jamal Elhasnaoui, Giulia Basile, Michele De Bortoli
Estrogen receptor-α (ERα) is a ligand-inducible protein which mediates estrogenic hormones signaling and defines the luminal BC phenotype. Recently, we demonstrated that even in absence of ligands ERα (apoERα) binds chromatin sites where it regulates transcription of several protein-coding and lncRNA genes. Noteworthy, apoERα-regulated lncRNAs marginally overlap estrogen-induced transcripts, thus representing a new signature of luminal BC genes. By the analysis of H3K27ac enrichment in hormone-deprived MCF-7 cells, we defined a set of Super Enhancers (SEs) occupied by apoERα, including one mapped in proximity of the DSCAM-AS1 lncRNA gene...
February 16, 2018: International Journal of Molecular Sciences
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
#15
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
#16
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
#17
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/29415456/bet-family-protein-brd4-an-emerging-actor-in-nf%C3%AE%C2%BAb-signaling-in-inflammation-and-cancer
#18
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
#19
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 that accounts for most skin cancer deaths. Among the physiological barriers against therapeutic success is a strong survival program driven by genes such as MITF that specify melanocyte identity, a phenomenon known in melanoma biology as lineage dependency. MITF overexpression is occasionally explained by gene amplification, but here we show that super-enhancers are also important determinants of MITF overexpression in some melanoma cell lines and tumors. Although compounds that directly inhibit MITF are unavailable, a covalent CDK7 inhibitor, THZ1, has recently been shown to potently suppress the growth of various cancers through the depletion of master transcription-regulating oncogenes and the disruption of their attendant super-enhancers...
February 8, 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
#20
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
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