Mechanisms of Commitment in Eukaryotic Cell Differentiation

• Applicant: Professor Dr. Wolfgang Marwan
• Subject Area: General Genetics and Functional Genome Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 508094520

The regulatory control of cell differentiation in eucaryotes is of fundamental importance with broad application potential in many aspects of regenerative medicine and biomedicine in general. Almost each non-infectious, chronic disease is caused by or associated with the dysregulation of cell differentiation or gene expression. It is known since a long time that the differentiation of eucaryotic cells depends on transcription factors. However, the regulatory circuits that control these transcription factors under physiological conditions in mediating the irreversible commitment to differentiation are largely unknown. There are even two competing views on the fundamental mechanistic principles that are unresolved since the early 1970ties: (1) The uproven, yet popular assumption of a well-defined step-by-step sequence of molecular events is challenged by (2) the dynamic systems perspective where commitment and differentiation occur on alternative routes through the so-called Waddington landscape as a result of stochasticity and non-linear behaviour of the underlying regulatory circuits. We make a new and entirely unconventional approach to resolve this long-standing controversy. Our project relies on repeated sampling of one and the same giant cell to obtain true single cell time series. Repeated sampling of the same cell is crucial for the unequivocal interpretation of gene expression changes over time. With the obtained data sets, ways to commitment to differentiation will be investigated, obtaining for the first time direct experimental evidence to resolve the molecular events associated with irreversible commitment and differentiation. As shown in Fig. 2, of the proposal, we will make a fundamental contribution in identifying commitment points and, with the help of our recently published purposefully developed computational data processing framework, discriminate alternative basic mechanisms of how commitment is achieved in an entirely data-driven manner.

• DFG Programme: Research Grants