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Offermann B, Knauer S, Singh A, et al. Boolean Modeling Reveals the Necessity of Transcriptional Regulation for Bistability in PC12 Cell Differentiation. Front Genet. 2016;7:44doi: 10.3389/fgene.2016.00044.
Offermann, B., Knauer, S., Singh, A., Fernández-Cachón, M. L., Klose, M., Kowar, S., Busch, H., & Boerries, M. (2016). Boolean Modeling Reveals the Necessity of Transcriptional Regulation for Bistability in PC12 Cell Differentiation. Frontiers in genetics, 744. https://doi.org/10.3389/fgene.2016.00044
Offermann, Barbara, et al. "Boolean Modeling Reveals the Necessity of Transcriptional Regulation for Bistability in PC12 Cell Differentiation." Frontiers in genetics vol. 7 (2016): 44. doi: https://doi.org/10.3389/fgene.2016.00044
Offermann B, Knauer S, Singh A, Fernández-Cachón ML, Klose M, Kowar S, Busch H, Boerries M. Boolean Modeling Reveals the Necessity of Transcriptional Regulation for Bistability in PC12 Cell Differentiation. Front Genet. 2016 Apr 14;7:44. doi: 10.3389/fgene.2016.00044. eCollection 2016. PMID: 27148350; PMCID: PMC4830832.
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Front Genet. 2016 Apr 14;7:44. doi: 10.3389/fgene.2016.00044. eCollection 2016.

Boolean Modeling Reveals the Necessity of Transcriptional Regulation for Bistability in PC12 Cell Differentiation.

Frontiers in genetics

Barbara Offermann, Steffen Knauer, Amit Singh, María L Fernández-Cachón, Martin Klose, Silke Kowar, Hauke Busch, Melanie Boerries

Affiliations

  1. Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg Freiburg, Germany.
  2. Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University FreiburgFreiburg, Germany; German Cancer ConsortiumFreiburg, Germany; German Cancer Research CenterHeidelberg, Germany.

PMID: 27148350 PMCID: PMC4830832 DOI: 10.3389/fgene.2016.00044

Abstract

The nerve growth factor NGF has been shown to cause cell fate decisions toward either differentiation or proliferation depending on the relative activity of downstream pERK, pAKT, or pJNK signaling. However, how these protein signals are translated into and fed back from transcriptional activity to complete cellular differentiation over a time span of hours to days is still an open question. Comparing the time-resolved transcriptome response of NGF- or EGF-stimulated PC12 cells over 24 h in combination with protein and phenotype data we inferred a dynamic Boolean model capturing the temporal sequence of protein signaling, transcriptional response and subsequent autocrine feedback. Network topology was optimized by fitting the model to time-resolved transcriptome data under MEK, PI3K, or JNK inhibition. The integrated model confirmed the parallel use of MAPK/ERK, PI3K/AKT, and JNK/JUN for PC12 cell differentiation. Redundancy of cell signaling is demonstrated from the inhibition of the different MAPK pathways. As suggested in silico and confirmed in vitro, differentiation was substantially suppressed under JNK inhibition, yet delayed only under MEK/ERK inhibition. Most importantly, we found that positive transcriptional feedback induces bistability in the cell fate switch. De novo gene expression was necessary to activate autocrine feedback that caused Urokinase-Type Plasminogen Activator (uPA) Receptor signaling to perpetuate the MAPK activity, finally resulting in the expression of late, differentiation related genes. Thus, the cellular decision toward differentiation depends on the establishment of a transcriptome-induced positive feedback between protein signaling and gene expression thereby constituting a robust control between proliferation and differentiation.

Keywords: Boolean modeling; EGF signaling; NGF signaling; PC12 cells; bistability

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