TY - JOUR
T1 - Application of Gene Expression Trajectories Initiated from ErbB Receptor Activation Highlights the Dynamics of Divergent Promoter Usage
AU - Carbajo, Daniel
AU - Magi, Shigeyuki
AU - Itoh, Masayoshi
AU - Kawaji, Hideya
AU - Lassmann, Timo
AU - Arner, Erik
AU - Forrest, Alistair R R
AU - Carninci, Piero
AU - Hayashizaki, Yoshihide
AU - Daub, Carsten O
AU - Okada-Hatakeyama, Mariko
AU - Mar, Jessica C
AU - Clevers, J.C.
AU - van de Wetering, M.L.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Breast Neoplasms
KW - Cell Cycle
KW - Cell Differentiation
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Enzyme Activation
KW - Epidermal Growth Factor
KW - ErbB Receptors
KW - Extracellular Signal-Regulated MAP Kinases
KW - Female
KW - Focal Adhesions
KW - Gene Expression
KW - Gene Expression Profiling
KW - Gene Expression Regulation
KW - Humans
KW - MAP Kinase Signaling System
KW - MCF-7 Cells
KW - Neuregulin-1
KW - Promoter Regions, Genetic
KW - Tumor Suppressor Protein p53
U2 - 10.1371/journal.pone.0144176
DO - 10.1371/journal.pone.0144176
M3 - Article
C2 - 26658111
SN - 1932-6203
VL - 10
SP - e0144176
JO - PLoS One
JF - PLoS One
IS - 12
ER -