Understanding epigenetic changes in aging stem cells – a computational model approach
Article first published online: 15 JAN 2014
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 2, pages 320–328, April 2014
How to Cite
Przybilla, J., Rohlf, T., Loeffler, M. and Galle, J. (2014), Understanding epigenetic changes in aging stem cells – a computational model approach. Aging Cell, 13: 320–328. doi: 10.1111/acel.12177
- Issue published online: 11 MAR 2014
- Article first published online: 15 JAN 2014
- Manuscript Accepted: 15 OCT 2013
- Federal Ministry of Education and Research (BMBF). Grant Number: FKZ 031 6065
- MAGE. Grant Number: 50500541
- aging of stem cells;
- clonal competition;
- DNA methylation;
- histone modification;
- mathematical model;
- population dynamics
During aging, a decline in stem cell function is observed in many tissues. This decline is accompanied by complex changes of the chromatin structure among them changes in histone modifications and DNA methylation which both affect transcription of a tissue-specific subset of genes. A mechanistic understanding of these age-associated processes, their interrelations and environmental dependence is currently lacking. Here, we discuss related questions on the molecular, cellular, and population level. We combine an individual cell-based model of stem cell populations with a model of epigenetic regulation of transcription. The novel model enables to simulate age-related changes of trimethylation of lysine 4 at histone H3 and of DNA methylation. These changes entail expression changes of genes that induce age-related phenotypes (ARPs) of cells. We compare age-related changes of regulatory states in quiescent stem cells occupying a niche with those observed in proliferating cells. Moreover, we analyze the impact of the activity of the involved epigenetic modifiers on these changes. We find that epigenetic aging strongly affects stem cell heterogeneity and that homing at stem cell niches retards epigenetic aging. Our model provides a mechanistic explanation how increased stem cell proliferation can lead to progeroid phenotypes. Adapting our model to properties observed for aged hematopoietic stem cell (HSC) clones, we predict that the hematopoietic ARP activates young HSCs and thereby retards aging of the entire HSC population. In addition, our model suggests that the experimentally observed high interindividual variance in HSC numbers originates in a variance of histone methyltransferase activity.