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https://www.readbyqxmd.com/read/29651155/epigenetic-activation-during-t-helper-17-cell-differentiation-is-mediated-by-tripartite-motif-containing-28
#1
Yu Jiang, Ying Liu, Huiping Lu, Shao-Cong Sun, Wei Jin, Xiaohu Wang, Chen Dong
Epigenetic regulation is important for T-cell fate decision. Although STAT3 is known to initiate Th17 differentiation program, the downstream mechanism is unclear. Here we show that Tripartite motif containing 28 (Trim28) expression in Th17 cells is required for Th17-mediated cytokine production and experimental autoimmune diseases. Genome-wide occupancy analysis reveals that TRIM28-bound regions overlap with almost all Th17-specific super-enhancers (SE), and that those SEs are impaired by the deficiency of STAT3 or TRIM28, but not of RORγt...
April 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29648668/widespread-enhancer-activation-via-er%C3%AE-mediates-estrogen-response-in-vivo-during-uterine-development
#2
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
#3
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/29625064/the-rules-of-successful-speed-dating-are-complex-even-for-super-enhancers
#4
Raymond Poot
Super-enhancers (SEs) are important for regulating cell identity genes and oncogenes, but correctly assigning target genes to SEs is difficult. Recently in Cell Reports, Lopes Novo et al. (2018) map interactions between SEs and promoters and observe a significant rewiring of complex SE-promoter networks between different pluripotent states.
April 5, 2018: Cell Stem Cell
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
#5
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/29555573/whole-exome-sequencing-identified-mutational-profiles-of-squamous-cell-carcinomas-of-anus
#6
Sun Shin, Hyeon-Chun Park, Min Sung Kim, Mi-Ryung Han, Sung Hak Lee, Seung Hyun Jung, Sug Hyung Lee, Yeun-Jun Chung
Anal squamous cell carcinoma (ASCC), either with human papillomavirus (HPV) (+) or (-), is a neoplastic disease with frequent recurrence and metastasis. To characterize ASCC genomes, we attempted to disclose novel alterations of ASCC genomes as well as other genetic features including mutation signatures. We performed whole-exome sequencing and copy number alteration (CNA) profiling for 8 ASCC samples from 6 patients (2 cases with primary and recurrent/metastatic tumors). We found known ASCC mutations (TP53, CDKN2A and PIK3CA) and CNAs (gains on 3q and 19q and losses on 11q and 13q)...
March 16, 2018: Human Pathology
https://www.readbyqxmd.com/read/29533787/loss-of-kdm6a-activates-super-enhancers-to-induce-gender-specific-squamous-like-pancreatic-cancer-and-confers-sensitivity-to-bet-inhibitors
#7
Jaclyn Andricovich, Stephanie Perkail, Yan Kai, Nicole Casasanta, Weiqun Peng, Alexandros Tzatsos
KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions...
March 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29528523/multiple-functional-variants-at-13q14-risk-locus-for-osteoporosis-regulate-rankl-expression-through-long-range-super-enhancer
#8
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
#9
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
#10
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
#11
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/29507293/dissecting-super-enhancer-hierarchy-based-on-chromatin-interactions
#12
Jialiang Huang, Kailong Li, Wenqing Cai, Xin Liu, Yuannyu Zhang, Stuart H Orkin, Jian Xu, Guo-Cheng Yuan
Recent studies have highlighted super-enhancers (SEs) as important regulatory elements for gene expression, but their intrinsic properties remain incompletely characterized. Through an integrative analysis of Hi-C and ChIP-seq data, here we find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers. Hub enhancers share similar histone marks with non-hub enhancers, but are distinctly associated with cohesin and CTCF binding sites and disease-associated genetic variants...
March 5, 2018: Nature Communications
https://www.readbyqxmd.com/read/29507187/depletion-of-mediator-kinase-module-subunits-represses-super-enhancer-associated-genes-in-colon-cancer-cells
#13
Emilia Kuuluvainen, Eva Domènech-Moreno, Elina H Niemelä, Tomi P Mäkelä
In cancer, oncogene activation is partly mediated by acquired super-enhancers therefore representing potential targets for inhibition. Super-enhancers are enriched for BRD4 and Mediator and both BRD4 and the Mediator MED12 subunit are disproportionally required for expression of super-enhancer associated genes in stem cells. Here, we find that depletion of Mediator kinase module subunits MED12, and MED13 with MED13L, can be used to reduce expression of cancer acquired super-enhancer genes such as MYC in colon cancer cells with a concomitant decrease in proliferation...
March 5, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29503092/yy1-positively-regulates-transcription-by-targeting-promoters-and-super-enhancers-through-the-baf-complex-in-embryonic-stem-cells
#14
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
#15
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
#16
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
#17
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/29471852/cdk9-inhibitors-in-acute-myeloid-leukemia
#18
REVIEW
Silvia Boffo, Angela Damato, Luigi Alfano, Antonio Giordano
Current treatment for acute myeloid leukemia (AML) is less than optimal, but increased understanding of disease pathobiology and genomics has led to clinical investigation of novel targeted therapies and rational combinations. Targeting the cyclin-dependent kinase 9 (CDK9) pathway, which is dysregulated in AML, is an attractive approach. Inhibition of CDK9 leads to downregulation of cell survival genes regulated by super enhancers such as MCL-1, MYC, and cyclin D1. As CDK9 inhibitors are nonselective, predictive biomarkers that may help identify patients most likely to respond to CDK9 inhibitors are now being utilized, with the goal of improving efficacy and safety...
February 23, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29462945/luminal-lncrnas-regulation-by-er%C3%AE-controlled-enhancers-in-a-ligand-independent-manner-in-breast-cancer-cells
#19
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
#20
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
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