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Sci Rep. 2018 Sep 3;8(1):13164. doi: 10.1038/s41598-018-30702-4.

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

Author information

1
Vascular Biology and Translational Research, School of Medical Sciences, University of New South Wales, Sydney, 2052, Australia.
2
RIKEN Center for Life Science Technologies (Division of Genomic Technologies) (CLST DGT), 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
3
Department of Biosciences and Nutrition and Science for Life Laboratory, Karolinska Institutet, SE-141 86, Stockholm, Sweden.
4
RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
5
RIKEN Omics Science Center (OSC), 1-7-22 Suehiro-cho, Tsurumi-ku Yokohama, 230-0045, Japan.
6
RIKEN Preventive Medicine and Diagnosis Innovation Program (PMI), 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
7
Preventive Medicine and Applied Genomics Unit, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
8
Laboratory for Applied Computational Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
9
Laboratory for Transcriptome Technology, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
10
Laboratory for Applied Regulatory Genomics Network Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, 230-0045, Japan.
11
Vascular Biology and Translational Research, School of Medical Sciences, University of New South Wales, Sydney, 2052, Australia. L.Khachigian@unsw.edu.au.

Abstract

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 FGF2 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.

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