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Promoter Usage and Dynamics in Vascular Smooth Muscle Cells Exposed to Fibroblast Growth Factor-2 or Interleukin-1β

Ahmad M. N. Alhendi, Margaret Patrikakis, Carsten O. Daub, Hideya Kawaji, Masayoshi Itoh, Michiel de Hoon, Piero Carninci, Yoshihide Hayashizaki, Erik Arner, Levon M. Khachigian
2018 Scientific Reports  
Smooth muscle cells (SMC) in blood vessels are normally growth quiescent and transcriptionally inactive. Our objective was to understand promoter usage and dynamics in SMC acutely exposed to a prototypic growth factor or pro-inflammatory cytokine. Using cap analysis gene expression (FANTOM5 project) we report differences in promoter dynamics for immediate-early genes (IEG) and other genes when SMC are exposed to fibroblast growth factor-2 or interleukin-1β. Of the 1871 promoters responding to
more » ... F2 or IL-1β considerably more responded to FGF2 (68.4%) than IL-1β (18.5%) and 13.2% responded to both. Expression clustering reveals sets of genes induced, repressed or unchanged. Among IEG responding rapidly to FGF2 or IL-1β were FOS, FOSB and EGR-1, which mediates human SMC migration. Motif activity response analysis (MARA) indicates most transcription factor binding motifs in response to FGF2 were associated with a sharp induction at 1 h, whereas in response to IL-1β, most motifs were associated with a biphasic change peaking generally later. MARA revealed motifs for FOS_FOS{B,L1}_JUN{B,D} and EGR-1..3 in the cluster peaking 1 h after FGF2 exposure whereas these motifs were in clusters peaking 1 h or later in response to IL-1β. Our findings interrogating CAGE data demonstrate important differences in promoter usage and dynamics in SMC exposed to FGF2 or IL-1β. Vascular smooth muscle cells (SMC) reside in normal arteries in a growth quiescent contractile state and respond to growth factors such as fibroblast growth factor-2 (FGF2) or pro-inflammatory cytokines such as interleukin-1β (IL-1β) which can arise from cellular and matrix trauma, infection, inflammation or platelet activation 1 . FGF2 and IL-1β have long been recognised as key mediators in SMC pathobiology. For example, neutralizing FGF2 antibodies reduce SMC proliferation induced by balloon catheterization by approximately 80% 2 . FGF2-driven SMC growth after balloon injury of carotid arteries is dependent on endogenous heparan sulfate proteoglycans 3 . Moreover the sulphated oligosaccharide PI-88 which binds FGF2 and blocks SMC proliferation inhibits intimal thickening after balloon injury 4 . Inhibition of FGF receptor signalling with the tyrosine kinase inhibitor SU5402 attenuates SMC and macrophage accumulation in atherosclerotic lesions in ApoE-deficient mice 5 . IL-1β can have autocrine growth effects on SMC 2,6 . The lack of IL-1β reduces the severity of atherosclerosis in ApoE-deficient
doi:10.1038/s41598-018-30702-4 pmid:30177712 pmcid:PMC6120868 fatcat:7dm5pwwpcvg3xo3pepro7k3kni

Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells

Erik Arner, Carsten O. Daub, Kristoffer Vitting-Seerup, Robin Andersson, Berit Lilje, Finn Drabløs, Andreas Lennartsson, Michelle Rönnerblad, Olga Hrydziuszko, Morana Vitezic, Tom C. Freeman, Ahmad M. N. Alhendi (+97 others)
2015 Science  
33. The use of microarray data sets to identify alternative mechanisms of TERT reactivation employed by those cell lines that were WT at positions -124 and -146 was unsuccessful. Average mRNA levels were roughly similar for (i) the ETS1 and ETS2 transcription factors (~1.1-fold higher in the WT group), (ii) the c-MYC transcription factor (~1.4-fold higher in the WT group), and (iii) the core components of the Polycomb repressive complex 2 (between~0.91-fold and~1.3-fold higher in the WT group).
more » ... 34. J. Nandakumar et al., Nature 492, 285-289 (2012). ACKNOWLEDGMENTS We thank C. Owens for providing the UC23, as well as detailed information on their origins and growth conditions. This work was supported by NIH grants CA075115 and CA104106 to D.T., Although it is generally accepted that cellular differentiation requires changes to transcriptional networks, dynamic regulation of promoters and enhancers at specific sets of genes has not been previously studied en masse. Exploiting the fact that active promoters and enhancers are transcribed, we simultaneously measured their activity in 19 human and 14 mouse time courses covering a wide range of cell types and biological stimuli. Enhancer RNAs, then messenger RNAs encoding transcription factors, dominated the earliest responses. Binding sites for key lineage transcription factors were simultaneously overrepresented in enhancers and promoters active in each cellular system. Our data support a highly generalizable model in which enhancer transcription is the earliest event in successive waves of transcriptional change during cellular differentiation or activation.
doi:10.1126/science.1259418 pmid:25678556 pmcid:PMC4681433 fatcat:wzkowgz4avg6jmd4pu5rcbnxh4

FANTOM5 CAGE profiles of human and mouse samples

Shuhei Noguchi, Takahiro Arakawa, Shiro Fukuda, Masaaki Furuno, Akira Hasegawa, Fumi Hori, Sachi Ishikawa-Kato, Kaoru Kaida, Ai Kaiho, Mutsumi Kanamori-Katayama, Tsugumi Kawashima, Miki Kojima (+166 others)
2017 Scientific Data  
In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis
more » ... pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.
doi:10.1038/sdata.2017.112 pmid:28850106 pmcid:PMC5574368 fatcat:cel5hhhtardinak67mbl2okvhe

Expressing functional siRNAs in mammalian cells using convergent transcription

Nham Tran, Murray J Cairns, Ian W Dawes, Greg M Arndt
2003 BMC Biotechnology  
We would like to thank Margaret Patrikakis for her technical assistance and other members of the High Throughput Genetics for comments on the manuscript.  ... 
doi:10.1186/1472-6750-3-21 pmid:14604435 pmcid:PMC280659 fatcat:54g66gtvofaz5pt24uavedw45e

Social media and our misconceptions of the realities

Richard Sanvenero
2013 Information & communications technology law  
Jones, 132 U.S. 945, 949 (2012). 145 Margaret Rouse, Global Positioning System (GPS), SEARCHMOBILECOMPUTING (May 2007), http://searchmobilecomputing.techtarget.com/definition/Global-Positioning-System.  ...  Patrikakis, Quantifying Privacy in Terms of Entropy for Context Aware Services, special issue of the Identity in the Information Society journal, "Identity Management in Grid and SOA", Springer, vol. 2  ... 
doi:10.1080/13600834.2013.805923 fatcat:kl6lkjbpxvah3hchvvtr3p5zbe