Thimo Rohlf (Max Planck Institute for Mathematics in the Sciences, University of Leipzig)
Abstract. Ageing is characterized by a gradual functional decline of virtually every tissue system and increased vulnerability and susceptibility to numerous diseases. Various experiments demonstrated that restrictions in regenerative mechanisms are fundamental in mammalian ageing, affecting whether tissue homeostasis can be maintained by the organism. These regenerative mechanisms predominately rely on an appropriately regulated balance between self-renewal and differentiation of functional adult stem cells. We suggest that imbalances in regeneration can be caused by instabilities of the stem cell epigenome, and 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. We first introduce a mathematical model of transcriptional regulation governed by histone modifications. This model describes binding of protein complexes to chromatin which are capable of reading and writing histone marks. Molecular interactions between these complexes, DNA and the histones create a regulatory switch of transcriptional activity possessing a regulatory memory. The regulatory states of the switch depend on the activity of histone (de-) methylases, the structure of the DNA-binding regions of the complexes, and the number of histones contributing to binding. We demonstrate how this mechanis can be exploited to couple cell proliferation and -differentiation. Finally, we extend the model by inluding DNA methylation, and discuss how the cooperative interplay between the different dynamical processes in the epigenome could contribute to irreversibility (and thereby ageing) in cell populations.