Execution of cell fate choice by cooperative gene activities

Development of higher eukaryotic organisms proceeds through a series of cell fate transitions, typically accompanied by a decline in developmental potency. Research in recent years has contributed to a substantial understanding of the molecular underpinnings of pluripotency. However, the mechanisms that compute cues from the cellular environment to elicit a regulated and exact cell fate choice are currently unknown. As a consequence, primary lineage decisions from mammalian pluripotent cells cannot be properly controlled experimentally. An interdisciplinary approach between the stem cell researchers from the group of Martin Leeb and computational biologists from the group of Andreas Beyer (University of Cologne) will focus on filling this gap in knowledge. In a first step we have systematically identified genes required for the differentiation of embryonic stem cells and used this information for a systems biology study to identify the key targets of more than 70 differentiation driver genes. One key finding was that no single gene seemed to be completely required for the exit from nave pluripotency, and even in the strongest mutants, only differentiation delays could be observed. This suggests extensive redundancy in the wiring of differentiation networks. In this project, we will systematically study epistasis between exit driver genes by developing novel 3D screening platforms and analysis pipelines. Our project will contribute to a deeper understanding of the mechanisms that drive and maintain cell identity and will identify the molecular reason for robustness in development.