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Super enhancer transcription

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https://www.readbyqxmd.com/read/29033324/the-elongation-factor-spt6-maintains-esc-pluripotency-by-controlling-super-enhancers-and-counteracting-polycomb-proteins
#1
A Hongjun Wang, Aster H Juan, Kyung Dae Ko, Pei-Fang Tsai, Hossein Zare, Stefania Dell'Orso, Vittorio Sartorelli
Spt6 coordinates nucleosome dis- and re-assembly, transcriptional elongation, and mRNA processing. Here, we report that depleting Spt6 in embryonic stem cells (ESCs) reduced expression of pluripotency factors, increased expression of cell-lineage-affiliated developmental regulators, and induced cell morphological and biochemical changes indicative of ESC differentiation. Selective downregulation of pluripotency factors upon Spt6 depletion may be mechanistically explained by its enrichment at ESC super-enhancers, where Spt6 controls histone H3K27 acetylation and methylation and super-enhancer RNA transcription...
October 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29024646/the-epstein-barr-virus-regulome-in-lymphoblastoid-cells
#2
Sizun Jiang, Hufeng Zhou, Jun Liang, Catherine Gerdt, Chong Wang, Liangru Ke, Stefanie C S Schmidt, Yohei Narita, Yijie Ma, Shuangqi Wang, Tyler Colson, Benjamin Gewurz, Guoliang Li, Elliott Kieff, Bo Zhao
Epstein-Barr virus (EBV) transforms B cells to continuously proliferating lymphoblastoid cell lines (LCLs), which represent an experimental model for EBV-associated cancers. EBV nuclear antigens (EBNAs) and LMP1 are EBV transcriptional regulators that are essential for LCL establishment, proliferation, and survival. Starting with the 3D genome organization map of LCL, we constructed a comprehensive EBV regulome encompassing 1,992 viral/cellular genes and enhancers. Approximately 30% of genes essential for LCL growth were linked to EBV enhancers...
October 11, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/29017057/a-p53-super-tumor-suppressor-reveals-a-tumor-suppressive-p53-ptpn14-yap-axis-in-pancreatic-cancer
#3
Stephano S Mello, Liz J Valente, Nitin Raj, Jose A Seoane, Brittany M Flowers, Jacob McClendon, Kathryn T Bieging-Rolett, Jonghyeob Lee, Danton Ivanochko, Margaret M Kozak, Daniel T Chang, Teri A Longacre, Albert C Koong, Cheryl H Arrowsmith, Seung K Kim, Hannes Vogel, Laura D Wood, Ralph H Hruban, Christina Curtis, Laura D Attardi
The p53 transcription factor is a critical barrier to pancreatic cancer progression. To unravel mechanisms of p53-mediated tumor suppression, which have remained elusive, we analyzed pancreatic cancer development in mice expressing p53 transcriptional activation domain (TAD) mutants. Surprisingly, the p53(53,54) TAD2 mutant behaves as a "super-tumor suppressor," with an enhanced capacity to both suppress pancreatic cancer and transactivate select p53 target genes, including Ptpn14. Ptpn14 encodes a negative regulator of the Yap oncoprotein and is necessary and sufficient for pancreatic cancer suppression, like p53...
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28991225/super-enhancers-define-a-proliferative-pgc-1%C3%AE-expressing-melanoma-subgroup-sensitive-to-bet-inhibition
#4
K A Gelato, L Schöckel, O Klingbeil, T Rückert, R Lesche, J Toedling, E Kalfon, M Héroult, P Lejeune, U Mönning, A E Fernández-Montalván, S Bäurle, S Siegel, B Haendler
Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1α is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1α levels are characteristic of the proliferative phenotype and are sensitive to bromodomain and extra-terminal domain (BET) inhibitor treatment. A super-enhancer region highly occupied by the BET family member BRD4 was identified for the PGC-1α gene...
October 9, 2017: Oncogene
https://www.readbyqxmd.com/read/28977473/dbcorc-a-database-of-core-transcriptional-regulatory-circuitries-modeled-by-h3k27ac-chip-seq-signals
#5
Moli Huang, Ye Chen, Manqiu Yang, Anyuan Guo, Ying Xu, Liang Xu, H Phillip Koeffler
Core transcription regulatory circuitry (CRC) is comprised of a small group of self-regulated transcription factors (TFs) and their interconnected regulatory loops. Studies from embryonic stem cells and other cellular models have revealed the elementary roles of CRCs in transcriptional control of cell identity and cellular fate. Systematic identification and subsequent archiving of CRCs across diverse cell types and tissues are needed to explore both cell/tissue type-specific and disease-associated transcriptional networks...
September 5, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28973462/analysis-of-primary-microrna-loci-from-nascent-transcriptomes-reveals-regulatory-domains-governed-by-chromatin-architecture
#6
Maria Bouvy-Liivrand, Ana Hernández de Sande, Petri Pölönen, Juha Mehtonen, Tapio Vuorenmaa, Henri Niskanen, Lasse Sinkkonen, Minna Unelma Kaikkonen, Merja Heinäniemi
Changes in mature microRNA (miRNA) levels that occur downstream of signaling cascades play an important role during human development and disease. However, the regulation of primary microRNA (pri-miRNA) genes remains to be dissected in detail. To address this, we followed a data-driven approach and developed a transcript identification, validation and quantification pipeline for characterizing the regulatory domains of pri-miRNAs. Integration of 92 nascent transcriptomes and multilevel data from cells arising from ecto-, endo- and mesoderm lineages reveals cell type-specific expression patterns, allows fine-resolution mapping of transcription start sites (TSS) and identification of candidate regulatory regions...
September 29, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28971975/tbx4-is-involved-in-the-super-enhancer-driven-transcriptional-programs-underlying-features-specific-to-lung-fibroblasts
#7
Masafumi Horie, Naoya Miyashita, Yu Mikami, Satoshi Noguchi, Yasuhiro Yamauchi, Maho Suzukawa, Takeshi Fukami, Ken Ohta, Yoshihide Asano, Shinichi Sato, Yoko Yamaguchi, Mitsuhiro Ohshima, Hiroshi Suzuki, Akira Saito, Takahide Nagase
Lung fibroblasts participate in the pathogenesis of respiratory diseases, including lung cancer and pulmonary fibrosis. Although fibroblasts are ubiquitous constituents of various organs, their cellular diversity among different organs has been poorly characterized. Here, we aimed to investigate the distinct gene signature of lung fibroblasts that represents its pulmonary origin, and the underlying gene regulatory networks. Promoter-level differential expression analysis by cap analysis of gene expression (CAGE) sequencing revealed distinct gene expression patterns of fibroblasts derived from different anatomical sites and identified 88 coding genes with higher expression in lung fibroblasts relative to other fibroblasts...
September 28, 2017: American Journal of Physiology. Lung Cellular and Molecular Physiology
https://www.readbyqxmd.com/read/28963353/somatic-super-enhancer-duplications-and-hotspot-mutations-lead-to-oncogenic-activation-of-the-klf5-transcription-factor
#8
Xiaoyang Zhang, Peter S Choi, Joshua M Francis, Galen F Gao, Joshua D Campbell, Aruna Ramachandran, Yoichiro Mitsuishi, Gavin Ha, Juliann Shih, Francisca Vazquez, Aviad Tsherniak, Alison M Taylor, Jin Zhou, Zhong Wu, Ashton C Berger, Marios Giannakis, William C Hahn, Andrew D Cherniack, Matthew Meyerson
The Krüppel-like family of transcription factors (KLF) plays critical roles in human development and is associated with cancer pathogenesis. KLF5 has been shown to promote cancer cell proliferation and tumorigenesis, and to be genomically amplified in cancer cells. We recently reported that the KLF5 gene is also subject to other types of somatic coding and noncoding genomic alterations in diverse cancer types. Here we show that these alterations activate KLF5 by three distinct mechanisms. 1) Focal amplification of super-enhancers activates KLF5 expression in squamous cell carcinomas...
September 29, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28955517/aff1-and-aff4-differentially-regulate-the-osteogenic-differentiation-of-human-mscs
#9
Chen-Chen Zhou, Qiu-Chan Xiong, Xin-Xing Zhu, Wen Du, Peng Deng, Xiao-Bing Li, Yi-Zhou Jiang, Shu-Juan Zou, Cun-Yu Wang, Quan Yuan
AFF1 and AFF4 belong to the AFF (AF4/FMR2) family of proteins, which function as scaffolding proteins linking two different transcription elongation factors, positive elongation factor b (P-TEFb) and ELL1/2, in super elongation complexes (SECs). Both AFF1 and AFF4 regulate gene transcription through elongation and chromatin remodeling. However, their function in the osteogenic differentiation of mesenchymal stem cells (MSCs) is unknown. In this study, we show that small interfering RNA (siRNA)-mediated depletion of AFF1 in human MSCs leads to increased alkaline phosphatase (ALP) activity, enhanced mineralization and upregulated expression of osteogenic-related genes...
2017: Bone Research
https://www.readbyqxmd.com/read/28951465/super-enhancers-promote-transcriptional-dysregulation-in-nasopharyngeal-carcinoma
#10
Jiang Yuan, Yan-Yi Jiang, Anand Mayakonda, Moli Huang, Ling-Wen Ding, Han Lin, Fenggang Yu, Yanan Lu, Thomas Kwok Seng Loh, Marilynn Chow, Samantha L Savage, Jeffrey W Tyner, De-Chen Lin, H Phillip Koeffler
Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southeast Asia and Southern China. The pathogenic mechanisms of NPC, particularly those involving epigenetic dysregulation, remain largely elusive, hampering clinical management of this malignancy. To identify novel druggable targets, we carried out an unbiased high-throughput chemical screening and observed that NPC cells were highly sensitive to inhibitors of cyclin-dependent kinases (CDK), especially THZ1, a covalent inhibitor of CDK7...
September 26, 2017: Cancer Research
https://www.readbyqxmd.com/read/28941026/transcription-instability-in-high-risk-neuroblastoma-is-associated-with-a-global-perturbation-of-chromatin-domains
#11
Carlo Zanon, Gian Paolo Tonini
Chromosome instability has a pivotal role among the hallmarks of cancer, but its transcriptional counterpart is rarely considered a relevant factor in cell destabilization. To examine transcription instability (TIN), we first devised a metric we named TIN index and used it to evaluate TIN on a dataset containing more than 500 neuroblastoma samples. We found that metastatic tumors from high-risk (HR) patients are characterized by significantly different TIN index values compared to low/intermediate-risk patients...
September 22, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28922346/grid-seq-reveals-the-global-rna-chromatin-interactome
#12
Xiao Li, Bing Zhou, Liang Chen, Lan-Tao Gou, Hairi Li, Xiang-Dong Fu
Higher eukaryotic genomes are bound by a large number of coding and non-coding RNAs, but approaches to comprehensively map the identity and binding sites of these RNAs are lacking. Here we report a method to capture in situ global RNA interactions with DNA by deep sequencing (GRID-seq), which enables the comprehensive identification of the entire repertoire of chromatin-interacting RNAs and their respective binding sites. In human, mouse, and Drosophila cells, we detected a large set of tissue-specific coding and non-coding RNAs that are bound to active promoters and enhancers, especially super-enhancers...
October 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28916725/characterization-of-enhancers-and-the-role-of-the-transcription-factor-klf7-in-regulating-corneal-epithelial-differentiation
#13
Rachel Herndon Klein, William Hu, Ghaidaa Kashgari, Ziguang Lin, Tuyen Nguyen, Michael Doan, Bogi Andersen
During tissue development, transcription factors bind regulatory DNA regions called enhancers, often located at great distances from the genes they regulate, to control gene expression. The enhancer landscape during embryonic stem cell differentiation has been well characterized. By contrast, little is known about the shared and unique enhancer regulatory mechanisms in different ectodermally derived epithelial cells. Here, we use ChIP-seq to identify domains enriched for histone marks H3K4me3, H3K4me1, and H3K27ac, and define for the first time the super enhancers and typical enhancers active in primary human corneal epithelial cells...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28910751/chromatin-reorganisation-in-epstein-barr-virus-infected-cells-and-its-role-in-cancer-development
#14
REVIEW
Michelle J West
The oncogenic Epstein-Barr virus (EBV) growth transforms B cells and drives lymphoma and carcinoma development. The virus encodes four key transcription factors (EBNA2, EBNA3A, EBNA3B and EBNA3C) that hijack host cell factors to bind gene control elements and reprogramme infected B cells. These viral factors predominantly target long-range enhancers to alter the expression of host cell genes that control B cell growth and survival and facilitate virus persistence. Enhancer and super-enhancer binding by these EBNAs results in large-scale reorganisation of three-dimensional enhancer-promoter architecture to drive the overexpression of oncogenes, the silencing of tumour suppressors and the modulation of transcription, cell-cycle progression, migration and adhesion...
September 11, 2017: Current Opinion in Virology
https://www.readbyqxmd.com/read/28892470/different-molecular-complexes-that-mediate-transcriptional-induction-and-repression-by-foxp3
#15
Ho-Keun Kwon, Hui-Min Chen, Diane Mathis, Christophe Benoist
FoxP3 conditions the transcriptional signature and functional facets of regulatory T cells (Treg cells). Its mechanism of action, whether as an activator or a repressor, has remained unclear. Here, chromatin analysis showed that FoxP3 bound active enhancer elements, not repressed chromatin, around loci over- or under-expressed in Treg cells. We evaluated the impact of a panel of FoxP3 mutants on its transcriptional activity and interactions with DNA, transcriptional cofactors and chromatin. Computational integration, confirmed by biochemical interaction and size analyses, showed that FoxP3 existed in distinct multimolecular complexes...
November 2017: Nature Immunology
https://www.readbyqxmd.com/read/28854182/expanding-the-effects-of-erg-on-chromatin-landscapes-and-dysregulated-transcription-in-prostate-cancer
#16
Deepak Babu, Melissa J Fullwood
ERG overexpression in prostate cancers promotes the development of widespread changes in gene expression and chromatin landscapes, leading to redistribution of key transcription factors in prostate cancers positive for the TMPRSS2-ERG fusion gene. The overexpression of ERG is further assisted by the development of a super-enhancer in the ERG locus.
August 30, 2017: Nature Genetics
https://www.readbyqxmd.com/read/28841410/in-situ-capture-of-chromatin-interactions-by-biotinylated-dcas9
#17
Xin Liu, Yuannyu Zhang, Yong Chen, Mushan Li, Feng Zhou, Kailong Li, Hui Cao, Min Ni, Yuxuan Liu, Zhimin Gu, Kathryn E Dickerson, Shiqi Xie, Gary C Hon, Zhenyu Xuan, Michael Q Zhang, Zhen Shao, Jian Xu
Cis-regulatory elements (CREs) are commonly recognized by correlative chromatin features, yet the molecular composition of the vast majority of CREs in chromatin remains unknown. Here, we describe a CRISPR affinity purification in situ of regulatory elements (CAPTURE) approach to unbiasedly identify locus-specific chromatin-regulating protein complexes and long-range DNA interactions. Using an in vivo biotinylated nuclease-deficient Cas9 protein and sequence-specific guide RNAs, we show high-resolution and selective isolation of chromatin interactions at a single-copy genomic locus...
August 24, 2017: Cell
https://www.readbyqxmd.com/read/28839111/super-lncrnas-identification-of-lncrnas-that-target-super-enhancers-via-rna-dna-dna-triplex-formation
#18
Benjamin Soibam
Super-enhancers are characterized by high levels of Mediator binding and are major contributors to the expression of their associated genes. They exhibit high levels of local chromatin interactions and a higher order of local chromatin organization. On the other hand, lncRNAs can localize to specific DNA sites by forming a RNA:DNA:DNA triplex, which in turn can contribute to local chromatin organization. In this paper, we characterize a new class of lncRNAs called super-lncRNAs that target super-enhancers and which can contribute to the local chromatin organization of the super-enhancers...
November 2017: RNA
https://www.readbyqxmd.com/read/28771803/a20-restores-phorbol-ester-induced-differentiation-of-thp-1-cells-in-the-absence-of-nuclear-factor-%C3%AE%C2%BAb-activation
#19
Miho Osako, Momoe Itsumi, Haruka Yamaguchi, Hiroaki Takeuchi, Shoji Yamaoka
A20, also referred to as tumor necrosis factor alpha (TNFα)-induced protein 3 (TNFAIP3), is an ubiquitin-editing enzyme whose expression is enhanced by NF-κB activation, and plays an important role in silencing NF-κB activity. Another well-known role for A20 is to protect cells from TNFα-induced apoptosis. Depletion of NF-κB in differentiating U937 monocytic leukemia cells is known to cause apoptotic cell death; however, much remains to be explored about the molecules that are expressed in an NF-κB-dependent manner and which support monocyte-macrophage differentiation...
August 3, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28740262/heterogeneity-of-neuroblastoma-cell-identity-defined-by-transcriptional-circuitries
#20
Valentina Boeva, Caroline Louis-Brennetot, Agathe Peltier, Simon Durand, Cécile Pierre-Eugène, Virginie Raynal, Heather C Etchevers, Sophie Thomas, Alban Lermine, Estelle Daudigeos-Dubus, Birgit Geoerger, Martin F Orth, Thomas G P Grünewald, Elise Diaz, Bertrand Ducos, Didier Surdez, Angel M Carcaboso, Irina Medvedeva, Thomas Deller, Valérie Combaret, Eve Lapouble, Gaelle Pierron, Sandrine Grossetête-Lalami, Sylvain Baulande, Gudrun Schleiermacher, Emmanuel Barillot, Hermann Rohrer, Olivier Delattre, Isabelle Janoueix-Lerosey
Neuroblastoma is a tumor of the peripheral sympathetic nervous system, derived from multipotent neural crest cells (NCCs). To define core regulatory circuitries (CRCs) controlling the gene expression program of neuroblastoma, we established and analyzed the neuroblastoma super-enhancer landscape. We discovered three types of identity in neuroblastoma cell lines: a sympathetic noradrenergic identity, defined by a CRC module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs); an NCC-like identity, driven by a CRC module containing AP-1 TFs; and a mixed type, further deconvoluted at the single-cell level...
September 2017: Nature Genetics
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