An ensemble approach for inferring semi-quantitative regulatory dynamics for the differentiation of mouse embryonic stem cells using prior knowledge

The process of differentiation of embryonic stem cells (ESCs) is currently becoming the focus of many systems biologists not only due to mechanistic interest but also since it is expected to play an increasingly important role in regenerative medicine, in particular with the advert to induced pluripotent stem cells. These ESCs give rise to the formation of the three germ layers and therefore to the formation of all tissues and organs. Here, we present a computational method for inferring regulatory interactions between the genes involved in ESC differentiation based on time resolved microarray profiles. Fully quantitative methods are commonly unavailable on such large-scale data; on the other hand, purely qualitative methods may fail to capture some of the more detailed regulations. Our method combines the beneficial aspects of qualitative and quantitative (ODE-based) modeling approaches searching for quantitative interaction coefficients in a discrete and qualitative state space. We further optimize on an ensemble of networks to detect essential properties and compare networks with respect to robustness. Applied to a toy model our method is able to reconstruct the original network and outperforms an entire discrete boolean approach. In particular, we show that including prior knowledge leads to more accurate results. Applied to data from differentiating mouse ESCs reveals new regulatory interactions, in particular we confirm the activation of Foxh1 through Oct4, mediating Nodal signaling.