Hall 123

Computational modelling of immune cell specification and reprogramming

Denis Thieffry

Institut de Biologie de l'École Normale Supérieure, Paris, France

Immune cells arise from a common set of hematopoietic stem cells, which differentiate hierarchically into the myeloid and lymphoid lineages. This process is tightly regulated by an intertwined network of transcription and epigenetic factors, which control the expression of gene programs to ensure cell commitment.
However, recent work on cellular reprogramming has demonstrated that the ectopic expression of specific factors can enforce the trans-differentiation of committed cells. For example, the transcription factor C/EBPa can induce the reprogramming of B-cells into macrophages. Although there is already a wealth of data on the molecular mechanisms by which specific hematopoietic genes are regulated, we are still lacking a global understanding of the interplay between these factors and how they control blood cell fate.
In order to integrate existing data in a common framework and test their consistency, we built a computational model of the regulatory network controlling B cell and macrophage specification from multipotent progenitors. We used a logical formalism which allow the modelling of large regulatory networks and the simulation of their dynamic in a qualitative way, in the absence of quantitative chemical data.
A first round of simulations led us to identify caveats in our first literature-derived model. To improve it, we performed a meta-analysis of all published ChIP-seq data targeting the factors present in our model (as well as from novel experiments). This allowed us to identify many potential regulations that were previously not documented. Using computational simulations, we tested in silico selected predicted interactions for their possible effect on cell fate, before validating them experimentally.