Application of gene expression trajectories initiated from ErbB receptor activation highlights the dynamics of divergent promoter usage

Daniel Carbajo, Shigeyuki Magi, Masayoshi Itoh, Hideya Kawaji, Timo Lassmann, Erik Arner, Alistair R R Forrest, Piero Carninci, Yoshihide Hayashizaki, Carsten O. Daub, Mariko Okada-Hatakeyama, Jessica C. Mar

Research output: Contribution to journalArticle

Abstract

Understanding how cells use complex transcriptional programs to alter their fate in response to specific stimuli is an important question in biology. For the MCF-7 human breast cancer cell line, we applied gene expression trajectory models to identify the genes involved in driving cell fate transitions. We modified trajectory models to account for the scenario where cells were exposed to different stimuli, in this case epidermal growth factor and heregulin, to arrive at different cell fates, i.e. proliferation and differentiation respectively. Using genome-wide CAGE time series data collected from the FANTOM5 consortium, we identified the sets of promoters that were involved in the transition of MCF-7 cells to their specific fates versus those with expression changes that were generic to both stimuli. Of the 1,552 promoters identified, 1,091 had stimulus-specific expression while 461 promoters had generic expression profiles over the time course surveyed. Many of these stimulus-specific promoters mapped to key regulators of the ERK (extracellular signal-regulated kinases) signaling pathway such as FHL2 (four and a half LIM domains 2). We observed that in general, generic promoters peaked in their expression early on in the time course, while stimulus- specific promoters tended to show activation of their expression at a later stage. The genes that mapped to stimulus-specific promoters were enriched for pathways that control focal adhesion, p53 signaling and MAPK signaling while generic promoters were enriched for cell death, transcription and the cell cycle. We identified 162 genes that were controlled by an alternative promoter during the time course where a subset of 37 genes had separate promoters that were classified as stimulus-specific and generic. The results of our study highlighted the degree of complexity involved in regulating a cell fate transition where multiple promoters mapping to the same gene can demonstrate quite divergent expression profiles.

Original languageEnglish (US)
Article numbere0144176
JournalPLoS One
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2015

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Gene expression
trajectories
Genes
Chemical activation
promoter regions
Trajectories
Gene Expression
gene expression
receptors
Neuregulin-1
Cells
Focal Adhesions
Extracellular Signal-Regulated MAP Kinases
MCF-7 Cells
Epidermal Growth Factor
cells
genes
Cell death
Transcription
Cell Cycle

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Application of gene expression trajectories initiated from ErbB receptor activation highlights the dynamics of divergent promoter usage. / Carbajo, Daniel; Magi, Shigeyuki; Itoh, Masayoshi; Kawaji, Hideya; Lassmann, Timo; Arner, Erik; Forrest, Alistair R R; Carninci, Piero; Hayashizaki, Yoshihide; Daub, Carsten O.; Okada-Hatakeyama, Mariko; Mar, Jessica C.

In: PLoS One, Vol. 10, No. 12, e0144176, 01.12.2015.

Research output: Contribution to journalArticle

Carbajo, D, Magi, S, Itoh, M, Kawaji, H, Lassmann, T, Arner, E, Forrest, ARR, Carninci, P, Hayashizaki, Y, Daub, CO, Okada-Hatakeyama, M & Mar, JC 2015, 'Application of gene expression trajectories initiated from ErbB receptor activation highlights the dynamics of divergent promoter usage', PLoS One, vol. 10, no. 12, e0144176. https://doi.org/10.1371/journal.pone.0144176
Carbajo, Daniel ; Magi, Shigeyuki ; Itoh, Masayoshi ; Kawaji, Hideya ; Lassmann, Timo ; Arner, Erik ; Forrest, Alistair R R ; Carninci, Piero ; Hayashizaki, Yoshihide ; Daub, Carsten O. ; Okada-Hatakeyama, Mariko ; Mar, Jessica C. / Application of gene expression trajectories initiated from ErbB receptor activation highlights the dynamics of divergent promoter usage. In: PLoS One. 2015 ; Vol. 10, No. 12.
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