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https://www.readbyqxmd.com/read/28868519/dynamic-change-of-transcription-pausing-through-modulating-nelf-protein-stability-regulates-granulocytic-differentiation
#1
Xiuli Liu, Aishwarya A Gogate, Melodi Tastemel, Venkat S Malladi, Huiyu Yao, Kim Nguyen, Lily Jun-Shen Huang, Xiaoying Bai
The NELF complex is a metazoan-specific factor essential for establishing transcription pausing. Although NELF has been implicated in cell fate regulation, the cellular regulation of NELF and its intrinsic role in specific lineage differentiation remains largely unknown. Using mammalian hematopoietic differentiation as a model system, here we identified a dynamic change of NELF-mediated transcription pausing as a novel mechanism regulating hematopoietic differentiation. We found a sharp decrease of NELF protein abundance upon granulocytic differentiation and a subsequent genome-wide reduction of transcription pausing...
August 8, 2017: Blood Advances
https://www.readbyqxmd.com/read/28825619/thermodynamic-modeling-of-gas-transport-in-glassy-polymeric-membranes
#2
Matteo Minelli, Giulio Cesare Sarti
Solubility and permeability of gases in glassy polymers have been considered with the aim of illustrating the applicability of thermodynamically-based models for their description and prediction. The solubility isotherms are described by using the nonequilibrium lattice fluid (NELF) (model, already known to be appropriate for nonequilibrium glassy polymers, while the permeability isotherms are described through a general transport model in which diffusivity is the product of a purely kinetic factor, the mobility coefficient, and a thermodynamic factor...
August 19, 2017: Membranes
https://www.readbyqxmd.com/read/28743741/cdk9-and-spt5-proteins-are-specifically-required-for-expression-of-herpes-simplex-virus-1-replication-dependent-late-genes
#3
Zhiyuan Zhao, Ka-Wei Tang, Isabella Muylaert, Tore Samuelsson, Per Elias
DNA replication greatly enhances expression of the herpes simplex virus 1 (HSV-1) γ2 late genes by still unknown mechanisms. Here, we demonstrate that 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB), an inhibitor of CDK9, suppresses expression of γ2 late genes with an IC50 of 5 μm, which is at least 10 times lower than the IC50 value required for inhibition of expression of early genes. The effect of DRB could not be explained by inhibition of DNA replication per se or loading of RNA polymerase II to late promoters and subsequent reduction of transcription...
September 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28697339/oncogenic-activation-of-the-rna-binding-protein-nelfe-and-myc-signaling-in-hepatocellular-carcinoma
#4
Hien Dang, Atsushi Takai, Marshonna Forgues, Yotsowat Pomyen, Haiwei Mou, Wen Xue, Debashish Ray, Kevin C H Ha, Quaid D Morris, Timothy R Hughes, Xin Wei Wang
Global transcriptomic imbalance is a ubiquitous feature associated with cancer, including hepatocellular carcinoma (HCC). Analyses of 1,225 clinical HCC samples revealed that a large numbers of RNA binding proteins (RBPs) are dysregulated and that RBP dysregulation is associated with poor prognosis. We further identified that oncogenic activation of a top candidate RBP, negative elongation factor E (NELFE), via somatic copy-number alterations enhanced MYC signaling and promoted HCC progression. Interestingly, NELFE induces a unique tumor transcriptome by selectively regulating MYC-associated genes...
July 10, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28578223/serpinb2-is-regulated-by-dynamic-interactions-with-pause-release-proteins-and-enhancer-rnas
#5
Lihua Shii, Li Song, Kelly Maurer, Zhe Zhang, Kathleen E Sullivan
The SERPINB2 gene is strongly upregulated in inflammatory states. In monocytes, it can constitute up to 1% of total cellular protein. It functions in protection from proteotoxic stress and plays a role in angioedema. The purpose of this study was to define the roles of enhancer RNAs embedded in the SERPIN gene complex. We found that the upstream enhancer RNAs upregulated SERPINB2 and the enhancer RNAs were expressed prior to those of SERPINB2 mRNA. Studies of the SERPINB2 promoter demonstrated the presence of an RNA polymerase II pause-inducing protein, NELF...
August 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28336775/nelf-e-is-recruited-to-dna-double-strand-break-sites-to-promote-transcriptional-repression-and-repair
#6
Samah W Awwad, Enas R Abu-Zhayia, Noga Guttmann-Raviv, Nabieh Ayoub
Double-strand breaks (DSBs) trigger rapid and transient transcription pause to prevent collisions between repair and transcription machineries at damage sites. Little is known about the mechanisms that ensure transcriptional block after DNA damage. Here, we reveal a novel role of the negative elongation factor NELF in blocking transcription activity nearby DSBs. We show that NELF-E and NELF-A are rapidly recruited to DSB sites. Furthermore, NELF-E recruitment and its repressive activity are both required for switching off transcription at DSBs...
May 2017: EMBO Reports
https://www.readbyqxmd.com/read/28213523/identification-of-regions-in-the-spt5-subunit-of-drb-sensitivity-inducing-factor-dsif-that-are-involved-in-promoter-proximal-pausing
#7
Yijun Qiu, David S Gilmour
DRB sensitivity-inducing factor (DSIF or Spt4/5) is a conserved transcription elongation factor that both inhibits and stimulates transcription elongation in metazoans. In Drosophila and vertebrates, DSIF together with negative elongation factor (NELF) associates with RNA polymerase II during early elongation and causes RNA polymerase II to pause in the promoter-proximal region of genes. The mechanism of how DSIF establishes pausing is not known. We constructed Spt5 mutant forms of DSIF and tested their capacity to restore promoter-proximal pausing to DSIF-depleted Drosophila nuclear extracts...
March 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28112367/knockdown-of-cobra1-decreases-the-proliferation-and-migration-of-hepatocellular-carcinoma-cells
#8
Eman El Zeneini, Sarah Kamel, Mahmoud El-Meteini, Asma Amleh
Cofactor of BRCA1 (COBRA1) is one of the four subunits that make up the negative elongation factor (NELF) complex that is involved in the stalling of RNA polymerase II early during transcription elongation. As such, it regulates the expression of a substantial number of genes involved in cell cycle control, cellular metabolism and DNA repair. With no DNA binding domain, its capacity to modulate gene expression occurs via its ability to interact with different transcription factors. In the field of cancer, its role is not yet fully understood...
March 2017: Oncology Reports
https://www.readbyqxmd.com/read/27863397/targeting-gli-by-gant61-involves-mechanisms-dependent-on-inhibition-of-both-transcription-and-dna-licensing
#9
Ruowen Zhang, Jiahui Wu, Sylvain Ferrandon, Katie J Glowacki, Janet A Houghton
The GLI genes are transcription factors and in cancers are oncogenes, aberrantly and constitutively activated. GANT61, a specific GLI inhibitor, has induced extensive cytotoxicity in human models of colon cancer. The FOXM1 promoter was determined to be a transcriptional target of GLI1. In HT29 cells, inhibition of GLI1 binding at the GLI consensus sequence by GANT61 led to inhibited binding of Pol II, the pause-release factors DSIF, NELF and p-TEFb. The formation of R-loops (RNA:DNA hybrids, ssDNA), were reduced by GANT61 at the FOXM1 promoter...
December 6, 2016: Oncotarget
https://www.readbyqxmd.com/read/27833949/the-emerging-picture-of-cdk9-p-tefb-more-than-20-years-of-advances-since-pitalre
#10
REVIEW
Nikolas Ferreira Dos Santos Paparidis, Maxwell Castro Durvale, Fernanda Canduri
CDK9 is a prominent member of the transcriptional CDKs subfamily, a group of kinases whose function is to control the primary steps of mRNA synthesis and processing by eukaryotic RNA polymerase II. As a cyclin-dependent kinase, CDK9 activation in vivo depends upon its association with T-type cyclins to assemble the positive transcription elongation factor (P-TEFb). Although CDK9/P-TEFb phosphorylates the C-terminal domain of RNAP II in the same positions targeted by CDK7 (TFIIH) and CDK8 (Mediator), the former does not participate in the transcription initiation, but rather plays a unique role by driving the polymerase to productive elongation...
January 31, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/27803842/what-do-we-learn-from-the-murine-jacob-nsmf-gene-knockout-for-human-disease
#11
Christina Spilker, Katarzyna M Grochowska, Michael R Kreutz
Mutations in the NSMF gene have been related to Kallmann syndrome. Conflicting results have been reported on the subcellular localization of Jacob/NELF, the protein encoded by the NSMF gene. Some reports indicate an extracellular localization and a function as a guidance molecule for migration of GnRH-positive neurons from the olfactory placode to the hypothalamus. Other studies have shown protein transport of Jacob from synapse-to-nucleus and indicate a role of the protein in neuronal activity-dependent gene expression...
2016: Rare Diseases
https://www.readbyqxmd.com/read/27716820/gdown1-associates-efficiently-with-rna-polymerase-ii-after-promoter-clearance-and-displaces-tfiif-during-transcript-elongation
#12
Elizabeth DeLaney, Donal S Luse
Pausing during the earliest stage of transcript elongation by RNA polymerase II (Pol II) is a nearly universal control point in metazoan gene expression. The substoichiometric Pol II subunit Gdown1 facilitates promoter proximal pausing in vitro in extract-based transcription reactions, out-competes the initiation/elongation factor TFIIF for binding to free Pol II and co-localizes with paused Pol II in vivo. However, we have shown that Gdown1 cannot functionally associate with the Pol II preinitiation complex (PIC), which contains TFIIF...
2016: PloS One
https://www.readbyqxmd.com/read/27468311/gaga-factor-a-positive-regulator-of-global-gene-expression-modulates-transcriptional-pausing-and-organization-of-upstream-nucleosomes
#13
Shih-Ying Tsai, Yuh-Long Chang, Krishna B S Swamy, Ruei-Lin Chiang, Der-Hwa Huang
BACKGROUND: Genome-wide studies in higher eukaryotes have revealed the presence of paused RNA polymerase II (RNA-Pol) at about 30-50 bp downstream of the transcription start site of genes involved in developmental control, cell proliferation and intercellular signaling. Promoter-proximal pausing is believed to represent a critical step in transcriptional regulation. GAGA sequence motifs have frequently been found in the upstream region of paused genes in Drosophila, implicating a prevalent binding factor, GAF, in transcriptional pausing...
2016: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/27353326/multiple-p-tefbs-cooperatively-regulate-the-release-of-promoter-proximally-paused-rna-polymerase-ii
#14
Xiaodong Lu, Xinxing Zhu, You Li, Min Liu, Bin Yu, Yu Wang, Muhua Rao, Haiyang Yang, Kai Zhou, Yao Wang, Yanheng Chen, Meihua Chen, Songkuan Zhuang, Lin-Feng Chen, Runzhong Liu, Ruichuan Chen
The association of DSIF and NELF with initiated RNA Polymerase II (Pol II) is the general mechanism for inducing promoter-proximal pausing of Pol II. However, it remains largely unclear how the paused Pol II is released in response to stimulation. Here, we show that the release of the paused Pol II is cooperatively regulated by multiple P-TEFbs which are recruited by bromodomain-containing protein Brd4 and super elongation complex (SEC) via different recruitment mechanisms. Upon stimulation, Brd4 recruits P-TEFb to Spt5/DSIF via a recruitment pathway consisting of Med1, Med23 and Tat-SF1, whereas SEC recruits P-TEFb to NELF-A and NELF-E via Paf1c and Med26, respectively...
August 19, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27282391/architecture-and-rna-binding-of-the-human-negative-elongation-factor
#15
Seychelle M Vos, David Pöllmann, Livia Caizzi, Katharina B Hofmann, Pascaline Rombaut, Tomasz Zimniak, Franz Herzog, Patrick Cramer
Transcription regulation in metazoans often involves promoter-proximal pausing of RNA polymerase (Pol) II, which requires the 4-subunit negative elongation factor (NELF). Here we discern the functional architecture of human NELF through X-ray crystallography, protein crosslinking, biochemical assays, and RNA crosslinking in cells. We identify a NELF core subcomplex formed by conserved regions in subunits NELF-A and NELF-C, and resolve its crystal structure. The NELF-AC subcomplex binds single-stranded nucleic acids in vitro, and NELF-C associates with RNA in vivo...
2016: ELife
https://www.readbyqxmd.com/read/27256882/chemical-genetic-discovery-of-parp-targets-reveals-a-role-for-parp-1-in-transcription-elongation
#16
Bryan A Gibson, Yajie Zhang, Hong Jiang, Kristine M Hussey, Jonathan H Shrimp, Hening Lin, Frank Schwede, Yonghao Yu, W Lee Kraus
Poly[adenosine diphosphate (ADP)-ribose] polymerases (PARPs) are a family of enzymes that modulate diverse biological processes through covalent transfer of ADP-ribose from the oxidized form of nicotinamide adenine dinucleotide (NAD(+)) onto substrate proteins. Here we report a robust NAD(+) analog-sensitive approach for PARPs, which allows PARP-specific ADP-ribosylation of substrates that is suitable for subsequent copper-catalyzed azide-alkyne cycloaddition reactions. Using this approach, we mapped hundreds of sites of ADP-ribosylation for PARPs 1, 2, and 3 across the proteome, as well as thousands of PARP-1-mediated ADP-ribosylation sites across the genome...
July 1, 2016: Science
https://www.readbyqxmd.com/read/27177472/mir-1236-regulates-hypoxia-induced-epithelial-mesenchymal-transition-and-cell-migration-invasion-through-repressing-senp1-and-hdac3
#17
Sung-Yuan Chen, Shu-Chun Teng, Tzu-Hao Cheng, Kou-Juey Wu
Intratumoral hypoxia induces epithelial-mesenchymal transition and promotes cancer metastasis. MicroRNAs (miRNAs) are endogenous, single-strand RNA molecules that regulate gene expression. MiRNAs control cell growth, proliferation, differentiation and cell death and may function as oncogenes or tumor suppressors. HDAC3 and SENP1 are two molecules involved in hypoxia-induced EMT and HIF-1α stability, respectively. In this report, we show that miR-1236 plays a critical role in hypoxia-induced EMT and metastasis...
August 1, 2016: Cancer Letters
https://www.readbyqxmd.com/read/26941120/genetic-suppression-reveals-dna-repair-independent-antagonism-between-brca1-and-cobra1-in-mammary-gland-development
#18
Sreejith J Nair, Xiaowen Zhang, Huai-Chin Chiang, Md Jamiul Jahid, Yao Wang, Paula Garza, Craig April, Neeraj Salathia, Tapahsama Banerjee, Fahad S Alenazi, Jianhua Ruan, Jian-Bing Fan, Jeffrey D Parvin, Victor X Jin, Yanfen Hu, Rong Li
The breast cancer susceptibility gene BRCA1 is well known for its function in double-strand break (DSB) DNA repair. While BRCA1 is also implicated in transcriptional regulation, the physiological significance remains unclear. COBRA1 (also known as NELF-B) is a BRCA1-binding protein that regulates RNA polymerase II (RNAPII) pausing and transcription elongation. Here we interrogate functional interaction between BRCA1 and COBRA1 during mouse mammary gland development. Tissue-specific deletion of Cobra1 reduces mammary epithelial compartments and blocks ductal morphogenesis, alveologenesis and lactogenesis, demonstrating a pivotal role of COBRA1 in adult tissue development...
March 4, 2016: Nature Communications
https://www.readbyqxmd.com/read/26813131/-association-of-the-extra-gonadal-manifestations-with-different-pathogenic-gene-mutations-in-male-patients-with-congenital-hypogonadotropic-hypogonadism
#19
Jiangfeng Mao, Rongrong Chen, Xueyan Wu, Zhaoxiang Liu, Junjie Zheng, Xi Wang, Min Nie, Jing Duan, Hongbing Zhang
OBJECTIVE: To explore the relationships between pathogenic gene mutations and extra-gonadal manifestations in male patients with congenital hypogonadotropic hypogonadism (CHH). METHODS: A total of 15 genes were screened in 259 CHH patients by massively parallel DNA sequencing. The identified pathogenic mutations were confirmed by Sanger polymerase chain reaction (PCR). The extra-gonadal features in all patients were recorded. RESULTS: Gene mutations were detected in 83 (32...
November 10, 2015: Zhonghua Yi Xue za Zhi [Chinese medical journal]
https://www.readbyqxmd.com/read/26549458/histone-deacetylases-positively-regulate-transcription-through-the-elongation-machinery
#20
Celeste B Greer, Yoshiaki Tanaka, Yoon Jung Kim, Peng Xie, Michael Q Zhang, In-Hyun Park, Tae Hoon Kim
Transcription elongation regulates the expression of many genes, including oncogenes. Histone deacetylase (HDAC) inhibitors (HDACIs) block elongation, suggesting that HDACs are involved in gene activation. To understand this, we analyzed nascent transcription and elongation factor binding genome-wide after perturbation of elongation with small molecule inhibitors. We found that HDACI-mediated repression requires heat shock protein 90 (HSP90) activity. HDACIs promote the association of RNA polymerase II (RNAP2) and negative elongation factor (NELF), a complex stabilized by HSP90, at the same genomic sites...
November 17, 2015: Cell Reports
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