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Promoter proximal pausing

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https://www.readbyqxmd.com/read/29187597/emerging-roles-of-transcriptional-enhancers-in-chromatin-looping-and-promoter-proximal-pausing-of-rna-polymerase-ii
#1
Huan Meng, Blaine Bartholomew
Initiation and regulation of transcription by RNA polymerase II (RNAPII) in eukaryotes relies upon the control elements of promoters and enhancers. Promoters and enhancers share common architectures and functions in similar ways. The prevailing view is functional promoters and enhancers can initiate bidirectional transcription. With the acceleration of recent genome-wide studies of regulated transcription, it has become clear that transcriptional enhancers in mammalian genomes are major sources of pervasive non-coding RNA transcription...
November 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29174978/transcription-pausing-regulates-mouse-embryonic-stem-cell-differentiation
#2
Melodi Tastemel, Aishwarya A Gogate, Venkat S Malladi, Kim Nguyen, Courtney Mitchell, Laura A Banaszynski, Xiaoying Bai
The pluripotency of embryonic stem cells (ESCs) relies on appropriate responsiveness to developmental cues. Promoter-proximal pausing of RNA polymerase II (Pol II) has been suggested to play a role in keeping genes poised for future activation. To identify the role of Pol II pausing in regulating ESC pluripotency, we have generated mouse ESCs carrying a mutation in the pause-inducing factor SPT5. Genomic studies reveal genome-wide reduction of paused Pol II caused by mutant SPT5 and further identify a tight correlation between pausing-mediated transcription effect and local chromatin environment...
November 16, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29056321/cbp-regulates-recruitment-and-release-of-promoter-proximal-rna-polymerase-ii
#3
Ann Boija, Dig Bijay Mahat, Aman Zare, Per-Henrik Holmqvist, Philge Philip, David J Meyers, Philip A Cole, John T Lis, Per Stenberg, Mattias Mannervik
Transcription activation involves RNA polymerase II (Pol II) recruitment and release from the promoter into productive elongation, but how specific chromatin regulators control these steps is unclear. Here, we identify a novel activity of the histone acetyltransferase p300/CREB-binding protein (CBP) in regulating promoter-proximal paused Pol II. We find that Drosophila CBP inhibition results in "dribbling" of Pol II from the pause site to positions further downstream but impedes transcription through the +1 nucleosome genome-wide...
November 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29037489/latent-hiv-1-tar-regulates-7sk-responsive-p-tefb-target-genes-and-targets-cellular-immune-responses-in-the-absence-of-tat
#4
Sebastian Eilebrecht, Bernd-Joachim Benecke, Arndt G Benecke
The transactivating response element (TAR) structure of the nascent HIV-1 transcript is critically involved in the recruitment of inactive positive transcription elongation factor b (P-TEFb) to the promoter proximal paused RNA polymerase II. The viral transactivator Tat is responsible for subsequent P-TEFb activation in order to start efficient viral transcription elongation. In the absence of the viral transactivator of transcription (Tat), e.g., during latency or in early stages of HIV transcription, TAR mediates an interaction of P-TEFb with its inhibitor hexamethylene bis-acetamide-inducible protein 1 (HEXIM1), keeping P-TEFb in its inactive form...
October 2017: Genomics, Proteomics & Bioinformatics
https://www.readbyqxmd.com/read/29017815/rna-polymerase-ii-pausing-and-transcriptional-regulation-of-the-hsp70-expression
#5
REVIEW
Heeyoun Bunch
Heat-shock proteins (HSPs) belong to the chaperone protein family whose expression is induced by different stresses including heat-shock. In response to the extracellular or intrinsic stimuli and stresses, HSPs play important roles in the maintenance of cellular homeostasis. HSP70, a major HSP protein (molecular weight, 70 KDa), regulates diverse cellular pathways including protein quality control, translation, immune response, and cancer survival. As a critical cellular defense system to minimize damages from cellular stresses, HSP70 expression and transcriptional activation are rapidly regulated, mainly through the action of a transcription activator, Heat shock factor 1 (HSF1)...
October 3, 2017: European Journal of Cell Biology
https://www.readbyqxmd.com/read/28994650/cdk9-dependent-rna-polymerase-ii-pausing-controls-transcription-initiation
#6
Saskia Gressel, Björn Schwalb, Tim Michael Decker, Weihua Qin, Heinrich Leonhardt, Dirk Eick, Patrick Cramer
Gene transcription can be activated by decreasing the duration of RNA polymerase II pausing in the promoter-proximal region, but how this is achieved remains unclear. Here we use a 'multi-omics' approach to demonstrate that the duration of polymerase pausing generally limits the productive frequency of transcription initiation in human cells ('pause-initiation limit'). We further engineer a human cell line to allow for specific and rapid inhibition of the P-TEFb kinase CDK9, which is implicated in polymerase pause release...
October 10, 2017: ELife
https://www.readbyqxmd.com/read/28985501/intragenic-enhancers-attenuate-host-gene-expression
#7
Senthilkumar Cinghu, Pengyi Yang, Justin P Kosak, Amanda E Conway, Dhirendra Kumar, Andrew J Oldfield, Karen Adelman, Raja Jothi
Eukaryotic gene transcription is regulated at many steps, including RNA polymerase II (Pol II) recruitment, transcription initiation, promoter-proximal Pol II pause release, and transcription termination; however, mechanisms regulating transcription during productive elongation remain poorly understood. Enhancers, which activate gene transcription, themselves undergo Pol II-mediated transcription, but our understanding of enhancer transcription and enhancer RNAs (eRNAs) remains incomplete. Here we show that transcription at intragenic enhancers interferes with and attenuates host gene transcription during productive elongation...
October 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28977633/oxidative-stress-rapidly-stabilizes-promoter-proximal-paused-pol-ii-across-the-human-genome
#8
Kyle A Nilson, Christine K Lawson, Nicholas J Mullen, Christopher B Ball, Benjamin M Spector, Jeffery L Meier, David H Price
Oxidative stress has pervasive effects on cells but how they respond transcriptionally upon the initial insult is incompletely understood. We developed a nuclear walk-on assay that semi-globally quantifies nascent transcripts in promoter-proximal paused RNA polymerase II (Pol II). Using this assay in conjunction with ChIP-Seq, in vitro transcription, and a chromatin retention assay, we show that within a minute, hydrogen peroxide causes accumulation of Pol II near promoters and enhancers that can best be explained by a rapid decrease in termination...
August 18, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28871058/the-hox-proteins-ubx-and-abda-collaborate-with-the-transcription-pausing-factor-m1bp-to-regulate-gene-transcription
#9
Amel Zouaz, Ankush Auradkar, Marie Claire Delfini, Meiggie Macchi, Marine Barthez, Serge Ela Akoa, Leila Bastianelli, Gengqiang Xie, Wu-Min Deng, Stuart S Levine, Yacine Graba, Andrew J Saurin
In metazoans, the pausing of RNA polymerase II at the promoter (paused Pol II) has emerged as a widespread and conserved mechanism in the regulation of gene transcription. While critical in recruiting Pol II to the promoter, the role transcription factors play in transitioning paused Pol II into productive Pol II is, however, little known. By studying how Drosophila Hox transcription factors control transcription, we uncovered a molecular mechanism that increases productive transcription. We found that the Hox proteins AbdA and Ubx target gene promoters previously bound by the transcription pausing factor M1BP, containing paused Pol II and enriched with promoter-proximal Polycomb Group (PcG) proteins, yet lacking the classical H3K27me3 PcG signature...
October 2, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28870425/emerging-insights-into-the-roles-of-the-paf1-complex-in-gene-regulation
#10
REVIEW
S Branden Van Oss, Christine E Cucinotta, Karen M Arndt
The conserved, multifunctional Polymerase-Associated Factor 1 complex (Paf1C) regulates all stages of the RNA polymerase (Pol) II transcription cycle. In this review, we examine a diverse set of recent studies from various organisms that build on foundational studies in budding yeast. These studies identify new roles for Paf1C in the control of gene expression and the regulation of chromatin structure. In exploring these advances, we find that various functions of Paf1C, such as the regulation of promoter-proximal pausing and development in higher eukaryotes, are complex and context dependent...
October 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28860207/paf1-regulation-of-promoter-proximal-pause-release-via-enhancer-activation
#11
Fei Xavier Chen, Peng Xie, Clayton K Collings, Kaixiang Cao, Yuki Aoi, Stacy A Marshall, Emily J Rendleman, Michal Ugarenko, Patrick A Ozark, Anda Zhang, Ramin Shiekhattar, Edwin R Smith, Michael Q Zhang, Ali Shilatifard
Gene expression in metazoans is regulated by RNA polymerase II (Pol II) promoter-proximal pausing and its release. Previously, we showed that Pol II-associated factor 1 (PAF1) modulates the release of paused Pol II into productive elongation. Here, we found that PAF1 occupies transcriptional enhancers and restrains hyperactivation of a subset of these enhancers. Enhancer activation as the result of PAF1 loss releases Pol II from paused promoters of nearby PAF1 target genes. Knockout of PAF1-regulated enhancers attenuates the release of paused Pol II on PAF1 target genes without major interference in the establishment of pausing at their cognate promoters...
September 22, 2017: Science
https://www.readbyqxmd.com/read/28851877/vegf-amplifies-transcription-through-ets1-acetylation-to-enable-angiogenesis
#12
Jiahuan Chen, Yi Fu, Daniel S Day, Ye Sun, Shiyan Wang, Xiaodong Liang, Fei Gu, Fang Zhang, Sean M Stevens, Pingzhu Zhou, Kai Li, Yan Zhang, Ruei-Zeng Lin, Lois E H Smith, Jin Zhang, Kun Sun, Juan M Melero-Martin, Zeguang Han, Peter J Park, Bing Zhang, William T Pu
Release of promoter-proximally paused RNA polymerase II (RNAPII) is a recently recognized transcriptional regulatory checkpoint. The biological roles of RNAPII pause release and the mechanisms by which extracellular signals control it are incompletely understood. Here we show that VEGF stimulates RNAPII pause release by stimulating acetylation of ETS1, a master endothelial cell transcriptional regulator. In endothelial cells, ETS1 binds transcribed gene promoters and stimulates their expression by broadly increasing RNAPII pause release...
August 29, 2017: Nature Communications
https://www.readbyqxmd.com/read/28811569/transcriptional-response-to-stress-is-pre-wired-by-promoter-and-enhancer-architecture
#13
Anniina Vihervaara, Dig Bijay Mahat, Michael J Guertin, Tinyi Chu, Charles G Danko, John T Lis, Lea Sistonen
Programs of gene expression are executed by a battery of transcription factors that coordinate divergent transcription from a pair of tightly linked core initiation regions of promoters and enhancers. Here, to investigate how divergent transcription is reprogrammed upon stress, we measured nascent RNA synthesis at nucleotide-resolution, and profiled histone H4 acetylation in human cells. Our results globally show that the release of promoter-proximal paused RNA polymerase into elongation functions as a critical switch at which a gene's response to stress is determined...
August 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28768201/human-tfiih-kinase-cdk7-regulates-transcription-associated-chromatin-modifications
#14
Christopher C Ebmeier, Benjamin Erickson, Benjamin L Allen, Mary A Allen, Hyunmin Kim, Nova Fong, Jeremy R Jacobsen, Kaiwei Liang, Ali Shilatifard, Robin D Dowell, William M Old, David L Bentley, Dylan J Taatjes
CDK7 phosphorylates the RNA polymerase II (pol II) C-terminal domain CTD and activates the P-TEFb-associated kinase CDK9, but its regulatory roles remain obscure. Here, using human CDK7 analog-sensitive (CDK7as) cells, we observed reduced capping enzyme recruitment, increased pol II promoter-proximal pausing, and defective termination at gene 3' ends upon CDK7 inhibition. We also noted that CDK7 regulates chromatin modifications downstream of transcription start sites. H3K4me3 spreading was restricted at gene 5' ends and H3K36me3 was displaced toward gene 3' ends in CDK7as cells...
August 1, 2017: Cell Reports
https://www.readbyqxmd.com/read/28717009/acetylation-on-histone-h3-lysine-9-mediates-a-switch-from-transcription-initiation-to-elongation
#15
Leah A Gates, Jiejun Shi, Aarti D Rohira, Qin Feng, Bokai Zhu, Mark T Bedford, Cari A Sagum, Sung Yun Jung, Jun Qin, Ming-Jer Tsai, Sophia Y Tsai, Wei Li, Charles E Foulds, Bert W O'Malley
The transition from transcription initiation to elongation is a key regulatory step in gene expression, which requires RNA polymerase II (pol II) to escape promoter proximal pausing on chromatin. Although elongation factors promote pause release leading to transcription elongation, the role of epigenetic modifications during this critical transition step is poorly understood. Two histone marks on histone H3, lysine 4 trimethylation (H3K4me3) and lysine 9 acetylation (H3K9ac), co-localize on active gene promoters and are associated with active transcription...
September 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28673542/bet-bromodomain-proteins-function-as-master-transcription-elongation-factors-independent-of-cdk9-recruitment
#16
Georg E Winter, Andreas Mayer, Dennis L Buckley, Michael A Erb, Justine E Roderick, Sarah Vittori, Jaime M Reyes, Julia di Iulio, Amanda Souza, Christopher J Ott, Justin M Roberts, Rhamy Zeid, Thomas G Scott, Joshiawa Paulk, Kate Lachance, Calla M Olson, Shiva Dastjerdi, Sophie Bauer, Charles Y Lin, Nathanael S Gray, Michelle A Kelliher, L Stirling Churchman, James E Bradner
Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation...
July 6, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28649985/attenuation-of-rna-polymerase-ii-pausing-mitigates-brca1-associated-r-loop-accumulation-and-tumorigenesis
#17
Xiaowen Zhang, Huai-Chin Chiang, Yao Wang, Chi Zhang, Sabrina Smith, Xiayan Zhao, Sreejith J Nair, Joel Michalek, Ismail Jatoi, Meeghan Lautner, Boyce Oliver, Howard Wang, Anna Petit, Teresa Soler, Joan Brunet, Francesca Mateo, Miguel Angel Pujana, Elizabeth Poggi, Krysta Chaldekas, Claudine Isaacs, Beth N Peshkin, Oscar Ochoa, Frederic Chedin, Constantine Theoharis, Lu-Zhe Sun, Tyler J Curiel, Richard Elledge, Victor X Jin, Yanfen Hu, Rong Li
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers...
June 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/28451632/skill-learning-modulates-rna-pol-ii-poising-at-immediate-early-genes-in-the-adult-striatum
#18
Pedro Galvão-Ferreira, Michal Lipinski, Fernando Santos, Angel Barco, Rui M Costa
A multilayered complexity of epigenetic and transcriptional regulatory mechanisms underlies neuronal activity-dependent gene transcription. The regulation of RNA Pol II progression along the transcription cycle, from promoter-proximal poising (with RNA Pol II paused at promoter-proximal regions, characterized by a Ser5P(+)-rich and Ser2P(+)-poor RPB1 CTD) to active elongation, has emerged as a major step in transcriptional regulation across several organisms, tissues, and developmental stages, including the nervous system...
March 2017: ENeuro
https://www.readbyqxmd.com/read/28396559/an-mrna-capping-enzyme-targets-fact-to-the-active-gene-to-enhance-the-engagement-of-rna-polymerase-ii-into-transcriptional-elongation
#19
Rwik Sen, Amala Kaja, Jannatul Ferdoush, Shweta Lahudkar, Priyanka Barman, Sukesh R Bhaumik
We have recently demonstrated that an mRNA capping enzyme, Cet1, impairs promoter-proximal accumulation/pausing of RNA polymerase II (Pol II) independently of its capping activity in Saccharomyces cerevisiae to control transcription. However, it is still unknown how Pol II pausing is regulated by Cet1. Here, we show that Cet1's N-terminal domain (NTD) promotes the recruitment of FACT (facilitates chromatin transcription that enhances the engagement of Pol II into transcriptional elongation) to the coding sequence of an active gene, ADH1, independently of mRNA-capping activity...
July 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28363125/pause-go-from-the-discovery-of-rna-polymerase-pausing-to-its-functional-implications
#20
REVIEW
Andreas Mayer, Heather M Landry, L Stirling Churchman
The synthesis of nascent RNA is a discontinuous process in which phases of productive elongation by RNA polymerase are interrupted by frequent pauses. Transcriptional pausing was first observed decades ago, but was long considered to be a special feature of transcription at certain genes. This view was challenged when studies using genome-wide approaches revealed that RNA polymerase II pauses at promoter-proximal regions in large sets of genes in Drosophila and mammalian cells. High-resolution genomic methods uncovered that pausing is not restricted to promoters, but occurs globally throughout gene-body regions, implying the existence of key-rate limiting steps in nascent RNA synthesis downstream of transcription initiation...
June 2017: Current Opinion in Cell Biology
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