Browsing by Author "Radde, Nicole E."

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Open Access
Bayesian estimation reveals that reproducible models in systems biology get more citations
(2023) Höpfl, Sebastian; Pleiss, Jürgen; Radde, Nicole E.
The Systems Biology community has taken numerous actions to develop data and modeling standards towards FAIR data and model handling. Nevertheless, the debate about incentives and rewards for individual researchers to make their results reproducible is ongoing. Here, we pose the specific question of whether reproducible models have a higher impact in terms of citations. Therefore, we statistically analyze 328 published models recently classified by Tiwari et al. based on their reproducibility. For hypothesis testing, we use a flexible Bayesian approach that provides complete distributional information for all quantities of interest and can handle outliers. The results show that in the period from 2013, i.e., 10 years after the introduction of SBML, to 2020, the group of reproducible models is significantly more cited than the non-reproducible group. We show that differences in journal impact factors do not explain this effect and that this effect increases with additional standardization of data and error model integration via PEtab. Overall, our statistical analysis demonstrates the long-term merits of reproducible modeling for the individual researcher in terms of citations. Moreover, it provides evidence for the increased use of reproducible models in the scientific community.
Open Access
Flanking sequences influence the activity of TET1 and TET2 methylcytosine dioxygenases and affect genomic 5hmC patterns
(2022) Adam, Sabrina; Bräcker, Julia; Klingel, Viviane; Osteresch, Bernd; Radde, Nicole E.; Brockmeyer, Jens; Bashtrykov, Pavel; Jeltsch, Albert
TET dioxygenases convert 5-methylcytosine (5mC) preferentially in a CpG context into 5-hydroxymethylcytosine (5hmC) and higher oxidized forms, thereby initiating DNA demethylation, but details regarding the effects of the DNA sequences flanking the target 5mC site on TET activity are unknown. We investigated oxidation of libraries of DNA substrates containing one 5mC or 5hmC residue in randomized sequence context using single molecule readout of oxidation activity and sequence and show pronounced 20 and 70-fold flanking sequence effects on the catalytic activities of TET1 and TET2, respectively. Flanking sequence preferences were similar for TET1 and TET2 and also for 5mC and 5hmC substrates. Enhanced flanking sequence preferences were observed at non-CpG sites together with profound effects of flanking sequences on the specificity of TET2. TET flanking sequence preferences are reflected in genome-wide and local patterns of 5hmC and DNA demethylation in human and mouse cells indicating that they influence genomic DNA modification patterns in combination with locus specific targeting of TET enzymes.
Open Access
Reversible switching and stability of the epigenetic memory system in bacteria
(2022) Graf, Dimitri; Laistner, Laura; Klingel, Viviane; Radde, Nicole E.; Weirich, Sara; Jeltsch, Albert
In previous work, we have developed a DNA methylation-based epigenetic memory system that operates in Escherichia coli to detect environmental signals, trigger a phenotypic switch of the cells and store the information in DNA methylation. The system is based on the CcrM DNA methyltransferase and a synthetic zinc finger (ZnF4), which binds DNA in a CcrM methylation-dependent manner and functions as a repressor for a ccrM gene expressed together with an egfp reporter gene. Here, we developed a reversible reset for this memory system by adding an increased concentration of ZnSO4 to the bacterial cultivation medium and demonstrate that one bacterial culture could be reversibly switched ON and OFF in several cycles. We show that a previously developed differential equation model of the memory system can also describe the new data. Then, we studied the long-term stability of the ON-state of the system over approximately 100 cell divisions showing a gradual loss of ON-state signal starting after 4 days of cultivation that is caused by individual cells switching from an ON- into the OFF-state. Over time, the methylation of the ZnF4-binding sites is not fully maintained leading to an increased OFF switching probability of cells, because stronger binding of ZnF4 to partially demethylated operator sites leads to further reductions in the cellular concentrations of CcrM. These data will support future design to further stabilize the ON-state and enforce the binary switching behaviour of the system. Together with the development of a reversible OFF switch, our new findings strongly increase the capabilities of bacterial epigenetic biosensors.
Open Access
A sphingolipid rheostat controls apoptosis versus apical cell extrusion as alternative tumour-suppressive mechanisms
(2024) Armistead, Joy; Höpfl, Sebastian; Goldhausen, Pierre; Müller-Hartmann, Andrea; Fahle, Evelin; Hatzold, Julia; Franzen, Rainer; Brodesser, Susanne; Radde, Nicole E.; Hammerschmidt, Matthias
Evasion of cell death is a hallmark of cancer, and consequently the induction of cell death is a common strategy in cancer treatment. However, the molecular mechanisms regulating different types of cell death are poorly understood. We have formerly shown that in the epidermis of hypomorphic zebrafish hai1a mutant embryos, pre-neoplastic transformations of keratinocytes caused by unrestrained activity of the type II transmembrane serine protease Matriptase-1 heal spontaneously. This healing is driven by Matriptase-dependent increased sphingosine kinase (SphK) activity and sphingosine-1-phosphate (S1P)-mediated keratinocyte loss via apical cell extrusion. In contrast, amorphic hai1afr26 mutants with even higher Matriptase-1 and SphK activity die within a few days. Here we show that this lethality is not due to epidermal carcinogenesis, but to aberrant tp53-independent apoptosis of keratinocytes caused by increased levels of pro-apoptotic C16 ceramides, sphingolipid counterparts to S1P within the sphingolipid rheostat, which severely compromises the epidermal barrier. Mathematical modelling of sphingolipid rheostat homeostasis, combined with in vivo manipulations of components of the rheostat or the ceramide de novo synthesis pathway, indicate that this unexpected overproduction of ceramides is caused by a negative feedback loop sensing ceramide levels and controlling ceramide replenishment via de novo synthesis. Therefore, despite their initial decrease due to increased conversion to S1P, ceramides eventually reach cell death-inducing levels, making transformed pre-neoplastic keratinocytes die even before they are extruded, thereby abrogating the normally barrier-preserving mode of apical live cell extrusion. Our results offer an in vivo perspective of the dynamics of sphingolipid homeostasis and its relevance for epithelial cell survival versus cell death, linking apical cell extrusion and apoptosis. Implications for human carcinomas and their treatments are discussed.