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Super enhancer transcription

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https://www.readbyqxmd.com/read/28420548/expression-of-long-non-coding-rnas-in-autoimmunity-and-linkage-to-enhancer-function-and-autoimmune-disease-risk-genetic-variants
#1
T M Aune, P S Crooke, A E Patrick, J T Tossberg, N J Olsen, C F Spurlock
Genome-wide association studies have identified numerous genetic variants conferring autoimmune disease risk. Most of these genetic variants lie outside protein-coding genes hampering mechanistic explorations. Numerous mRNAs are also differentially expressed in autoimmune disease but their regulation is also unclear. The majority of the human genome is transcribed yet its biologic significance is incompletely understood. We performed whole genome RNA-sequencing [RNA-seq] to categorize expression of mRNAs, known and novel long non-coding RNAs [lncRNAs] in leukocytes from subjects with autoimmune disease and identified annotated and novel lncRNAs differentially expressed across multiple disorders...
April 15, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28407486/transcriptional-elongation-of-hsv-immediate-early-genes-by-the-super-elongation-complex-drives-lytic-infection-and-reactivation-from-latency
#2
Roberto Alfonso-Dunn, Anne-Marie W Turner, Pierre M Jean Beltran, Jesse H Arbuckle, Hanna G Budayeva, Ileana M Cristea, Thomas M Kristie
The cellular transcriptional coactivator HCF-1 is required for initiation of herpes simplex virus (HSV) lytic infection and for reactivation from latency in sensory neurons. HCF-1 stabilizes the viral Immediate Early (IE) gene enhancer complex and mediates chromatin transitions to promote IE transcription initiation. In infected cells, HCF-1 was also found to be associated with a network of transcription elongation components including the super elongation complex (SEC). IE genes exhibit characteristics of genes controlled by transcriptional elongation, and the SEC-P-TEFb complex is specifically required to drive the levels of productive IE mRNAs...
April 12, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28398509/mll3-mll4-are-required-for-cbp-p300-binding-on-enhancers-and-super-enhancer-formation-in-brown-adipogenesis
#3
Binbin Lai, Ji-Eun Lee, Younghoon Jang, Lifeng Wang, Weiqun Peng, Kai Ge
Histone H3K4me1/2 methyltransferases MLL3/MLL4 and H3K27 acetyltransferases CBP/p300 are major enhancer epigenomic writers. To understand how these epigenomic writers orchestrate enhancer landscapes in cell differentiation, we have profiled genomic binding of MLL4, CBP, lineage-determining transcription factors (EBF2, C/EBPβ, C/EBPα, PPARγ), coactivator MED1, RNA polymerase II, as well as epigenome (H3K4me1/2/3, H3K9me2, H3K27me3, H3K36me3, H3K27ac), transcriptome and chromatin opening during adipogenesis of immortalized preadipocytes derived from mouse brown adipose tissue (BAT)...
April 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28373363/re-engineering-the-pancreas-tumor-microenvironment-a-regenerative-program-hacked
#4
EDITORIAL
Gerard I Evan, Nasun Hah, Trevor D Littlewood, Nicole M Sodir, Tania Campos, Michael Downes, Ronald M Evans
The "hallmarks" of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks...
April 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28369649/functional-anatomy-of-the-immunoglobulin-heavy-chain-3%C3%AE-super-enhancer-needs-not-only-core-enhancer-elements-but-also-their-unique-dna-context
#5
Sandrine Le Noir, François Boyer, Sandrine Lecardeur, Mylène Brousse, Zeliha Oruc, Jeanne Cook-Moreau, Yves Denizot, Michel Cogné
Cis-regulatory elements feature clustered sites for transcription factors, defining core enhancers and have inter-species homology. The mouse IgH 3΄ regulatory region (3'RR), a major B-cell super-enhancer, consists of four of such core enhancers, scattered throughout more than 25 kb of packaging 'junk DNA', the sequence of which is not conserved but follows a unique palindromic architecture which is conserved in all mammalian species. The 3'RR promotes long-range interactions and potential IgH loops with upstream promoters, controlling class switch recombination (CSR) and somatic hypermutation (SHM)...
March 22, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28369050/antagonism-of-b-cell-enhancer-networks-by-stat5-drives-leukemia-and-poor-patient-survival
#6
Casey D S Katerndahl, Lynn M Heltemes-Harris, Mark J L Willette, Christine M Henzler, Seth Frietze, Rendong Yang, Hilde Schjerven, Kevin A T Silverstein, Laura B Ramsey, Gregory Hubbard, Andrew D Wells, Roland P Kuiper, Blanca Scheijen, Frank N van Leeuwen, Markus Müschen, Steven M Kornblau, Michael A Farrar
The transcription factor STAT5 has a critical role in B cell acute lymphoblastic leukemia (B-ALL). How STAT5 mediates this effect is unclear. Here we found that activation of STAT5 worked together with defects in signaling components of the precursor to the B cell antigen receptor (pre-BCR), including defects in BLNK, BTK, PKCβ, NF-κB1 and IKAROS, to initiate B-ALL. STAT5 antagonized the transcription factors NF-κB and IKAROS by opposing regulation of shared target genes. Super-enhancers showed enrichment for STAT5 binding and were associated with an opposing network of transcription factors, including PAX5, EBF1, PU...
April 3, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28359147/functional-enhancers-as-master-regulators-of-tissue-specific-gene-regulation-and-cancer-development
#7
REVIEW
Je Yeong Ko, Sumin Oh, Kyung Hyun Yoo
Tissue-specific transcription is critical for normal development, and abnormalities causing undesirable gene expression may lead to diseases such as cancer. Such highly organized transcription is controlled by enhancers with specific DNA sequences recognized by transcription factors. Enhancers are associated with chromatin modifications that are distinct epigenetic features in a tissue-specific manner. Recently, super-enhancers comprising enhancer clusters co-occupied by lineage-specific factors have been identified in diverse cell types such as adipocytes, hair follicle stem cells, and mammary epithelial cells...
March 2017: Molecules and Cells
https://www.readbyqxmd.com/read/28351896/enhancers-and-chromatin-structures-regulatory-hubs-in-gene-expression-and-diseases
#8
Zhenhua Hu, Wee Wei Tee
Gene expression requires successful communication between enhancer and promoter regions, whose activities are regulated by a variety of factors and associated with distinct chromatin structures; in addition, functionally related genes and their regulatory repertoire tend to be arranged in the same sub-chromosomal regulatory domains. In this review, we discuss the importance of enhancers, especially clusters of enhancers (such as super-enhancers), as key regulatory hubs to integrate environmental cues and encode spatiotemporal instructions for genome expression, which are critical for a variety of biological processes governing mammalian development...
March 28, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28350987/the-super-elongation-complex-drives-neural-stem-cell-fate-commitment
#9
Kun Liu, Dan Shen, Jingwen Shen, Shihong M Gao, Bo Li, Chouin Wong, Weidong Feng, Yan Song
Asymmetric stem cell division establishes an initial difference between a stem cell and its differentiating sibling, critical for maintaining homeostasis and preventing carcinogenesis. Yet the mechanisms that consolidate and lock in such initial fate bias remain obscure. Here, we use Drosophila neuroblasts to demonstrate that the super elongation complex (SEC) acts as an intrinsic amplifier to drive cell fate commitment. SEC is highly expressed in neuroblasts, where it promotes self-renewal by physically associating with Notch transcription activation complex and enhancing HES (hairy and E(spl)) transcription...
March 27, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28348365/e%C3%AE-and-3-rr-igh-enhancers-show-hierarchic-unilateral-dependence-in-mature-b-cells
#10
A Saintamand, C Vincent-Fabert, M Marquet, N Ghazzaui, V Magnone, E Pinaud, M Cogné, Y Denizot
Enhancer and super-enhancers are master regulators of cell fate. While they act at long-distances on adjacent genes, it is unclear whether they also act on one another. The immunoglobulin heavy chain (IgH) locus is unique in carrying two super-enhancers at both ends of the constant gene cluster: the 5'Eμ super-enhancer promotes VDJ recombination during the earliest steps of B-cell ontogeny while the 3' regulatory region (3'RR) is essential for late differentiation. Since they carry functional synergies in mature B-cells and physically interact during IgH locus DNA looping, we investigated if they were independent engines of locus remodelling or if their function was more intimately intermingled, their optimal activation then requiring physical contact with each other...
March 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28340338/a-phase-separation-model-for-transcriptional-control
#11
REVIEW
Denes Hnisz, Krishna Shrinivas, Richard A Young, Arup K Chakraborty, Phillip A Sharp
Phase-separated multi-molecular assemblies provide a general regulatory mechanism to compartmentalize biochemical reactions within cells. We propose that a phase separation model explains established and recently described features of transcriptional control. These features include the formation of super-enhancers, the sensitivity of super-enhancers to perturbation, the transcriptional bursting patterns of enhancers, and the ability of an enhancer to produce simultaneous activation at multiple genes. This model provides a conceptual framework to further explore principles of gene control in mammals...
March 23, 2017: Cell
https://www.readbyqxmd.com/read/28340332/super-elongation-complex-promotes-early-hiv-transcription-and-its-function-is-modulated-by-p-tefb
#12
Alona Kuzmina, Simona Krasnopolsky, Ran Taube
Early work on the control of transcription of the human immunodeficiency virus (HIV) laid the foundation for our current knowledge of how RNA Polymerase II is released from promoter-proximal pausing sites and transcription elongation is enhanced. The viral Tat activator recruits Positive Transcription Elongation Factor b (P-TEFb) and Super Elongation Complex (SEC) that jointly drive transcription elongation. While substantial progress in understanding the role of SEC in HIV gene transcription elongation has been obtained, defining of the mechanisms that govern SEC functions is still limited, and the role of SEC in controlling HIV transcription in the absence of Tat is less clear...
February 17, 2017: Transcription
https://www.readbyqxmd.com/read/28335007/a-class-of-circadian-long-non-coding-rnas-mark-enhancers-modulating-long-range-circadian-gene-regulation
#13
Zenghua Fan, Meng Zhao, Parth D Joshi, Ping Li, Yan Zhang, Weimin Guo, Yichi Xu, Haifang Wang, Zhihu Zhao, Jun Yan
Circadian rhythm exerts its influence on animal physiology and behavior by regulating gene expression at various levels. Here we systematically explored circadian long non-coding RNAs (lncRNAs) in mouse liver and examined their circadian regulation. We found that a significant proportion of circadian lncRNAs are expressed at enhancer regions, mostly bound by two key circadian transcription factors, BMAL1 and REV-ERBα. These circadian lncRNAs showed similar circadian phases with their nearby genes. The extent of their nuclear localization is higher than protein coding genes but less than enhancer RNAs...
March 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28329684/cis-regulatory-circuits-regulating-nek6-kinase-overexpression-in-transformed-b-cells-are-super-enhancer-independent
#14
Yue Huang, Olivia I Koues, Jiang-Yang Zhao, Regina Liu, Sarah C Pyfrom, Jacqueline E Payton, Eugene M Oltz
Alterations in distal regulatory elements that control gene expression underlie many diseases, including cancer. Epigenomic analyses of normal and diseased cells have produced correlative predictions for connections between dysregulated enhancers and target genes involved in pathogenesis. However, with few exceptions, these predicted cis-regulatory circuits remain untested. Here, we dissect cis-regulatory circuits that lead to overexpression of NEK6, a mitosis-associated kinase, in human B cell lymphoma. We find that only a minor subset of predicted enhancers is required for NEK6 expression...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28323209/sox9-a-genomic-view-of-tissue-specific-expression-and-action
#15
Aleisha Symon, Vincent Harley
The SOX9 transcription factor controls the differentiation of many cell types among vertebrates. The SOX9 gene locus is large and complex and contains various tissue-specific enhancers. Individual enhancers direct specific expression of SOX9 in chondrocytes, Sertoli cells and cranial neural crest cells. Human SOX9 mutations can lead to either the complete Campomelic Dysplasia syndrome, or isolated clinical features, depending upon whether the mutation occurs in the coding region or in enhancer regions. Chromatin Immunoprecipitation has helped to define SOX9 control of target gene expression at the genome wide level in hair follicle stem cells and in chondrocytes where SOX9 binds at super-enhancers...
March 16, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28299664/roles-of-runx-in-b-cell-immortalisation
#16
Michelle J West, Paul J Farrell
RUNX1 and RUNX3 are the main RUNX genes expressed in B lymphocytes. Both are expressed throughout B-cell development and play key roles at certain key developmental transitions. The tumour-associated Epstein-Barr virus (EBV) has potent B-cell transforming ability and manipulates RUNX3 and RUNX1 transcription through novel mechanisms to control B cell growth. In contrast to resting mature B cells where RUNX1 expression is high, in EBV-infected cells RUNX1 levels are low and RUNX3 levels are high. Downregulation of RUNX1 in these cells results from cross-regulation by RUNX3 and serves to relieve RUNX1-mediated growth repression...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28299656/roles-of-the-runx1-enhancer-in-normal-hematopoiesis-and-leukemogenesis
#17
Wei-Siang Liau, Phuong Cao Thi Ngoc, Takaomi Sanda
Enhancers are regulatory elements in genomic DNA that contain specific sequence motifs that are bound by DNA-binding transcription factors. The activity of enhancers is tightly regulated in an integrated and combinatorial manner, thus yielding complex patterns of transcription in different tissues. Identifying enhancers is crucial to understanding the physiological and pathogenic roles of their target genes. The RUNX1 intronic enhancer, eR1, acts in cis to regulate RUNX1 gene expression in hematopoietic stem cells (HSCs) and hemogenic endothelial cells...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28283057/super-enhancer-mediated-rna-processing-revealed-by-integrative-microrna-network-analysis
#18
Hiroshi I Suzuki, Richard A Young, Phillip A Sharp
Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function...
March 9, 2017: Cell
https://www.readbyqxmd.com/read/28273065/complex-multi-enhancer-contacts-captured-by-genome-architecture-mapping
#19
Robert A Beagrie, Antonio Scialdone, Markus Schueler, Dorothee C A Kraemer, Mita Chotalia, Sheila Q Xie, Mariano Barbieri, Inês de Santiago, Liron-Mark Lavitas, Miguel R Branco, James Fraser, Josée Dostie, Laurence Game, Niall Dillon, Paul A W Edwards, Mario Nicodemi, Ana Pombo
The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation)...
March 23, 2017: Nature
https://www.readbyqxmd.com/read/28262751/the-swi-snf-chromatin-remodelling-complex-is-required-for-maintenance-of-lineage-specific-enhancers
#20
Burak H Alver, Kimberly H Kim, Ping Lu, Xiaofeng Wang, Haley E Manchester, Weishan Wang, Jeffrey R Haswell, Peter J Park, Charles W M Roberts
Genes encoding subunits of SWI/SNF (BAF) chromatin remodelling complexes are collectively altered in over 20% of human malignancies, but the mechanisms by which these complexes alter chromatin to modulate transcription and cell fate are poorly understood. Utilizing mouse embryonic fibroblast and cancer cell line models, here we show via ChIP-seq and biochemical assays that SWI/SNF complexes are preferentially targeted to distal lineage specific enhancers and interact with p300 to modulate histone H3 lysine 27 acetylation...
March 6, 2017: Nature Communications
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