Cell Plasticity - Systems Biology of Cell Differentiation
The goal of the Cell Plasticity project is to develop a systems-level understanding of the gene regulatory networks that are responsible for cellular differentiation in mammals. We will focus in particular on elucidating and modeling the mechanisms by which the sequence-specific binding of transcription factors interacts with the dynamics of the epigenetic code along the genome, i.e. the local status of chromatin as determined by histone and DNA modifications.
In order to derive general regulatory principles we propose to study a panel of mouse cellular differentiation systems including four normal differentiation processes and two cancer-related transformation events. All these systems have well-defined time courses of differentiation with clearly defined cellular states that allow collection of homogeneous populations of cells.
To study this panel of mouse differentiation systems we will apply uniform measurement protocols and data processing procedures to obtain genome-wide time courses of mRNA expression, miRNA expression, histone modifications, DNA methylation and selected transcription factor binding, for each model system. The data from all systems will be analyzed by common novel mathematical and computational methods. In particular, we will use sophisticated methods for genome-wide annotation of transcription factor binding sites in combination with the time course data to develop quantitative models for the genome-wide interactions between chromatin state and the actions of sequence-specific transcription factors.
Predictions from the computational models will be followed-up and validated by targeted perturbation experiments using mutant animals and cells, as well as knock-down or over-expression of transcription factors and chromatin modifying enzymes. Our final goal is to develop novel models of the transcriptional and epigenetic regulatory networks acting in these differentiation systems to the point that we can engineer them. That is, we aim to predict and confirm particular perturbations that reliably trans-differentiate a system from a given start state to a desired target state.
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