About Us - Research
The Systems Biology of Cell Plasticity in Health and Disease is an RTD project funded by the SystemsX.ch initiative. Coordinated by Dr. Susan Gasser, Cell Plasticity brings together 8 research teams, and several affiliated members. The common goal is to decode the regulation of stem cell status and cell differentiation, under both physiological and pathological conditions. Specifically, we will delineate genome-wide epigenetic and transcriptional events that occur during cell differentiation using systematic, quantitative approaches. We will relate this insight to gene regulation programs that have been computationally predicted and experimentally tested. In particular, we will model the interplay of transcription factor activities and chromatin modifications during cell differentiation by genetic perturbations in our experimental systems (hematopoiesis, neurogenesis, and the epithelial-mesenchymal transition). Ultimately, by performing the proposed integrated analysis, we aim to generate predictive models for the epigenetic contribution to the state of pluripotency and to cell differentiation.
Research
To achieve the goals of Cell Plasticity, we will focus exclusively on mouse systems and enforce strict standards of sample preparation and data generation. The experiments will be driven in large part by modeling and computational considerations. Core laboratories will carry out the defined projects and are committed to sharing resources, expertise, biological systems, reagents, and technological knowledge relevant to the described research goal. In many cases this will entail the training of selected postdocs interested in the goals of Cell Plasticity.Cell Plasticity will collaborate with and complement the efforts of D-BSSE (ETH Department of Biosystems Science and Engineering in Basel) in the maintenance of a recently established deep sequencing platform (Solexa Illumina instruments). This core facility ensures uniformly high-quality, genome-wide data for computational analysis. Developing algorithms for scoring genome-wide epigenetic mark distribution and the interpretation of gene expression/modification patterns through defined differentiation steps will be achieved through close interactions with the computational scientists of Cell Plasticity. These efforts will focus on the role of epigenetic modifications in the regulation of cell plasticity and stem cell differentiation exploiting mouse as our model system.
Cell differentiation involves large-scale changes in gene expression. Much of these are implemented by a concerted interplay between sequence-specific binding of transcription factors to regulatory motifs of genes and reprogramming of the epigenetic state of chromatin.
The main aim of our research is to uncover general organizational principles in this interplay by comparing different cellular systems. To discover these general principles, we study cell differentiation in a number of model systems in which transcriptional regulation and epigenetic programming are thought to play a major role. These are hematopoiesis, neurogenesis and tumor metastasis.
Uniform high-throughput methodologies will be applied to each model system to ensure that experimental data from these different systems can be compared quantitatively. The types of modifications we will monitor include DNA methylation state, binding data for specific transcription factors and distribution of specific histone variants and modification states, as well as mRNA and miRNA expression levels. We will obtain time courses of such measurements during the cellular differentiation processes of interest, wherever possible genome-wide, and we will collect such data both for wild-type and relevant conditional knock-out mice.
Recent techniques like Chromatin-IP and MeDIP enable genome-wide analysis of epigenetic marks and miRNA expression (see Mohn et al., Mol Cell, 2008).
The data will be analyzed using sophisticated computational approaches. We will interpret binding data in terms of the occurrence of specific combinations of regulatory motifs and the accessibility of the DNA to the relevant factors. We will model how the interplay between the epigenetic state of the chromatin and the binding of specific transcription factors determines expression levels. The ultimate goal is to develop general models of feedback loops between DNA accessibility, transcription factor binding, and the recruitment of chromatin modifiers that specify transcriptional activation or silencing.
Example of an informatics analysis of epigenetic data and transcription factor binding sites (Suzuki et al., Nat Genet. 2009 May;41(5):553-62)
