WorldCat Identities

Offermann, Barbara

Overview
Works: 2 works in 4 publications in 1 language and 21 library holdings
Roles: Author
Publication Timeline
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Most widely held works by Barbara Offermann
Transcriptome dynamics to unravel PC12 cell fate decisions by Barbara Offermann( )

3 editions published between 2016 and 2017 in English and held by 18 WorldCat member libraries worldwide

Abstract: The PC12 cell line is a well-established cell model system for analysing cell fate decisionmaking processes. When stimulated with the growth factor EGF the cells proliferate increasingly, when stimulated with the nerve growth factor NGF the cells differentiate into sympathetic-like neurons. Both processes are regulated via the ERK/MAPK pathway. In this context, signal duration of activated ERK seems to be the key mechanism for the emergence of the distinct cell fates. Whereas NGF stimulation results in sustained ERK activation and neuronal differentiation of the cell line, EGF stimulation activates ERK transiently and results in enhanced cell proliferation. How the temporal dynamics of ERK signalling are encoded and translated in order to specify cell fates has not been fully understood yet. <br>This thesis is the first comparison of the EGF and NGF induced transcriptome of PC12 cells on a time scale of 24 hours with high sample density. It was shown that the EGF and NGF stimulus activate a very similar set of genes, which initiates and modulates the cell fate decision. These genes' expression dynamics, however, were different depending on the stimulus used: EGF stimulation induced a short impulse-like gene expression pattern, whereas NGF stimulation resulted in a long-sustained response. In line with previous studies it was demonstrated, that immediate early genes such as Egr1, Fos and Junb show an increased stability in the case of NGF stimulation. It was shown, that this is most likely due to a delayed negative transcriptional feedback via Fosl1, Atf3, Maff, Klf2 und Zfp36l2. Moreover it was demonstrated, that both cell fates, proliferation as well as differentiation, are not solely dependent on the ERK/MAPK pathway. Within the first hour after stimulation with EGF cross-talk between the MAPK and PI3K pathways seems necessary in order to induce enhanced cell proliferation. After stimulation with NGF a more complex and sequential activation of different pathways was identified. In this context the activation of the Il6 pathway and the uPA/uPAR complex seems to be of special importance. The activation of these two pathways was exclusively seen after NGF-stimulation, which encourages further research to gain a deeper understanding of their function in the process of neuronal differentiation. Additionally, Dusp6 was identified as a potentially important modulator of the PC12 cell fate. In summary, this thesis analyses and compares the EGF and NGF induced transcriptome of PC12 cells from a systems biology perspective. Most importantly, it was shown, that the activation of a similar set of genes may result in distinctly different cellular behaviour depending on the genes' expression dynamics
Boolean modeling reveals the necessity of transcriptional regulation for bistability in PC12 cell differentiation by Barbara Offermann( )

1 edition published in 2016 in English and held by 3 WorldCat member libraries worldwide

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
 
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Alternative Names
Offermann, Barbara Inga Veronika

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