AUTHOR=Floettmann Max , Scharp Till , Klipp Edda 

TITLE=A Stochastic Model of Epigenetic Dynamics in Somatic Cell Reprogramming

JOURNAL=Frontiers in Physiology

VOLUME=Volume 3 - 2012

YEAR=2012

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2012.00216

DOI=10.3389/fphys.2012.00216

ISSN=1664-042X

ABSTRACT=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 reproduces
experimentally observed reprogramming efficiencies and changes in
methylation and chromatin remodeling. It enables us to investigate in detail,
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.
Simulation results show good reproduction of experimental observations during
reprogramming, despite the simple stucture of the model. An extensive
analysis and introduced variations hint towards 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.