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Promoter proximal pausing

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https://www.readbyqxmd.com/read/29017815/rna-polymerase-ii-pausing-and-transcriptional-regulation-of-the-hsp70-expression
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
https://www.readbyqxmd.com/read/28360925/jmjd6-a-jmjc-dioxygenase-with-many-interaction-partners-and-pleiotropic-functions
#17
REVIEW
Janice Kwok, Marie O'Shea, David A Hume, Andreas Lengeling
Lysyl hydroxylation and arginyl demethylation are post-translational events that are important for many cellular processes. The jumonji domain containing protein 6 (JMJD6) has been reported to catalyze both lysyl hydroxylation and arginyl demethylation on diverse protein substrates. It also interacts directly with RNA. This review summarizes knowledge of JMJD6 functions that have emerged in the last 15 years and considers how a single Jumonji C (JmjC) domain-containing enzyme can target so many different substrates...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28340332/super-elongation-complex-promotes-early-hiv-transcription-and-its-function-is-modulated-by-p-tefb
#18
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...
May 27, 2017: Transcription
https://www.readbyqxmd.com/read/28273906/identifying-novel-transcriptional-and-epigenetic-features-of-nuclear-lamina-associated-genes
#19
Feinan Wu, Jie Yao
Because a large portion of the mammalian genome is associated with the nuclear lamina (NL), it is interesting to study how native genes resided there are transcribed and regulated. In this study, we report unique transcriptional and epigenetic features of nearly 3,500 NL-associated genes (NL genes). Promoter regions of active NL genes are often excluded from NL-association, suggesting that NL-promoter interactions may repress transcription. Active NL genes with higher RNA polymerase II (Pol II) recruitment levels tend to display Pol II promoter-proximal pausing, while Pol II recruitment and Pol II pausing are not correlated among non-NL genes...
December 2017: Scientific Reports
https://www.readbyqxmd.com/read/28263964/total-rna-seq-to-identify-pharmacological-effects-on-specific-stages-of-mrna-synthesis
#20
Sarah A Boswell, Andrew Snavely, Heather M Landry, L Stirling Churchman, Jesse M Gray, Michael Springer
Pharmacological perturbation is a powerful tool for understanding mRNA synthesis, but identification of the specific steps of this multi-step process that are targeted by small molecules remains challenging. Here we applied strand-specific total RNA sequencing (RNA-seq) to identify and distinguish specific pharmacological effects on transcription and pre-mRNA processing in human cells. We found unexpectedly that the natural product isoginkgetin, previously described as a splicing inhibitor, inhibits transcription elongation...
May 2017: Nature Chemical Biology
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