The objective of the Young Investigator Group MAGE is to develop and validate a mathematical model of stem cell ageing. Our approach bases on the observation of an unstable stem cell epigenome. In our group, we combine expertise in the fields of stem cell biology, molecular biology of evolution, quantitative analysis of transcriptional data and multi-scale agent-based modelling. This gives us the opportunity to follow a systems biology approach to stem cell ageing that explains age-related phenomena at the cellular and tissue level by complex molecular scenarios of transcriptional regulation.

We propose that alterations of the epigenome in course of the ageing process are driven by soft inheritance of epigenetic marks and continuous imprinting induced by changing environments. Thus, we will focus on unravelling the dynamics of these processes. For this purpose we analyze data on transcriptional regulation and epigenetic marks in embryonal and somatic stem cells in order to generate functional maps of the stem cell epigenome. We integrate genome–wide data on histone modifications, DNA methylation and RNA-transcription obtained in ongoing international epigenome projects.

This analysis will support the design of a model of transcriptional regulation that includes beside cis-regulatory networks the regulatory subsystems of histone modifications and DNA-methylation considering their specific cooperativity. In contrast to common top-down approaches we follow a bottom-up approach to transcriptional regulation based on statistical thermodynamics. We link all regulatory modules in the framework of an artificial genome-based approach. In simulation series of the mathematical model we will identify generic changes of the chromatin structure after extensive replication and frequent adaptation of the modification machinery to environmental cues. The results provide insights into stability, fluctuations and drifts of the regulatory states and will enable us to predict potential changes within the aged epigenome that can be reproducibly detected in experiments. To validate these predictions and to sequentially refine our model, we will analyze epigenetic changes in ageing cell systems. As available data sets may not comprise all the necessary information, we aim at experimentally complementing selected data sets using the original samples. These experiments will be performed by our experimental partners. After careful validation of our model, we plan to do an exemplary experimental study on human mesenchymal stem cells (MSCs). Related experiments are advised in the framework of the large scale project "LIFE" of the University of Leipzig. Moreover, our results will enable us to identify essential molecular features that have to be covered by individual cell-based models of the spatio-temporal organisation of stem cell populations. These features will be integrated into individual cell-based modelling framework already established at the University of Leipzig. This then enables future model types that will be capable of predicting stem cell organisation in ageing individuals with respect to different environments. Thus, the project supports current general technologies and methodologies in systems biology to close the gap between the molecular, cellular and tissue level to describe living systems.
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