The stem cell epigenome is characterized by a sensitive balance between
de- and modification processes of the chromatin. During cancer development and ageing this balance becomes disturbed and results in characteristic changes of
the epigenome which induce different gene expression pattern. Among these changes the most frequently investigated are changes of DNA-methylation.

Several experimental studies demonstrated that during both, cancer development and ageing, specific groups of CpGs become hyper-methylated while others become
hypo-methylated compared to their normal methylation state. These changes are known to be functional relevant as they affect also the transcription of associated genes. Thereby, silenced genes can become active and former activated genes can become  silenced. On the basis of such DNA-methylation pattern it is possible to classify subtypes of a cancer and predict the patient outcomes.

Here, we introduce a new multi-scale computer model (Przybilla et al., 2013, Przybilla et al., 2014) that enables simulation of these epigenetic processes on the molecular, cellular and population level. We model cell populations where each cell contains an artificial genome encoding for round about 100 genes.Transcriptional regulation of these genes is controlled by cis-regulatory networks, trimethylation of lysine 4 (H3K4me3) and lysine 9 (H3K9me3) and DNA methylation.

We apply the model in order to provide a mechanistic explanation of parallel local hyper- and global hypo-methylation during cancer development and ageing. For
this purpose, we analyze how persistent proliferation activity and mutations that change specific histone modifiers impact DNA methylation profiles.

We find that spontaneous loss of H3K4me3 (H3K9me3) during cell replication can induce hyper-  and hypo-methlyation. Enhanced proliferation during cancer
development enforces these epigenetic drifts that can be, in parallel, modified by mutations of chromatin modifiers. We present some typical simulations scenarios that are consistent with experimental findings in colorectal cancer and glioblastoma.

Przybilla J, Buske P, Binder H, Galle J, Histone modifications control DNA methylation profiles during ageing and tumour expansion, Frontiers in Life Science,Vol.7,Iss. 1-2, 2013, p.31-43.

Przybilla J, Rohlf T, Loeffler M, Galle J, Understanding epigenetic changes in aging stem cells – a computational model approach, Aging Cell, 2014, DOI:10.1111/acel.12177