A stochastic model of epigenetic dynamics in somatic cell reprogramming
- Department of Biology, Theoretical Biophysics, Humboldt-Universität zu Berlin, Berlin, Germany
Somatic cell reprogramming has dramatically changed stem cell research in recent years. The high pace of new findings in the field and an ever increasing amount of data from new high throughput techniques make it challenging to isolate core principles of the process. In order to analyze such mechanisms, we developed an abstract mechanistic model of a subset of the known regulatory processes during cell differentiation and production of induced pluripotent stem cells. This probabilistic Boolean network describes the interplay between gene expression, chromatin modifications, and DNA methylation. The model incorporates recent findings in epigenetics and partially reproduces experimentally observed reprogramming efficiencies and changes in methylation and chromatin remodeling. It enables us to investigate, how the temporal progression of the process is regulated. It also explicitly includes the transduction of factors using viral vectors and their silencing in reprogrammed cells, since this is still a standard procedure in somatic cell reprogramming. Based on the model we calculate an epigenetic landscape for probabilities of cell states. Simulation results show good reproduction of experimental observations during reprogramming, despite the simple structure of the model. An extensive analysis and introduced variations hint toward possible optimizations of the process that could push the technique closer to clinical applications. Faster changes in DNA methylation increase the speed of reprogramming at the expense of efficiency, while accelerated chromatin modifications moderately improve efficiency.
Keywords: differentiation and reprogramming, epigenetic landscape, induced pluripotent stem cells, mathematical modeling, probabilistic Boolean network
Citation: Flöttmann M, Scharp T and Klipp E (2012) A stochastic model of epigenetic dynamics in somatic cell reprogramming. Front. Physio. 3:216. doi: 10.3389/fphys.2012.00216
Received: 16 February 2012; Paper pending published: 01 April 2012;
Accepted: 30 May 2012; Published online: 27 June 2012.
Copyright: © 2012 Flöttmann, Scharp and Klipp. This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
*Correspondence: Edda Klipp, Department of Biology, Theoretical Biophysics, Humboldt-Universität zu Berlin, Invalidenstraße 42, Berlin D-10115, Germany. e-mail: email@example.com