Project description
Uncovering the mechanisms of cell fate determination
The goal of the EU-funded FateID project is to uncover the mechanisms behind cell fate specification and the preceding epigenetic states. The researchers aim to develop a novel strategy for the simultaneous profiling of the many factors involved in gene regulation in a single cell. Its implementation will provide insights into transcriptional controls, revealing the causal relationships between histone modifications, their spatial positioning within the nucleus and Polycomb group proteins. Next, the researchers will try to apply a “molecular memory” strategy to obtain recordings of past regulatory states, followed by single-cell analysis methods to unravel the gene regulation mechanisms that govern lineage determination in early mouse development.
Objective
The establishment of cell type-specific transcriptional programs involves many interconnected regulatory mechanisms acting on different genomic scales. To dissect this multi-layered control of gene expression in detail, I will develop methods that a) measure multiple cellular outputs in single cells, and b) obtain that information in a time-resolved manner. This proposal outlines my approach to study early mouse development at numerous levels, including (but not limited to) transcription, chromatin context, and nuclear organization. In doing so, I expect to shed light on the mechanism behind cell fate specification and the epigenetic states that precede it.
I will develop a novel strategy to simultaneously profile many factors involved in gene regulation in the same cell. Its successful implementation will give insight into transcriptional control at unprecedented modality, revealing the causal relationships between histone modifications, spatial positioning within the nucleus, Polycomb group proteins, and others. Next, I will pursue several “molecular memory” strategies to obtain recordings of past regulatory states, followed by multi-omic readouts at later developmental times. Such retrospective analyses enable linking fate decisions to past molecular events in the same cell, thereby permitting careful reconstruction of the molecular trajectories underlying cell fate choice. Finally, these and previously developed single-cell methods will be applied to unravel the gene-regulatory mechanisms that govern lineage determination in early mouse development.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
1011 JV AMSTERDAM
Netherlands