Project description
The role of epigenetic modifiers in establishing cell fate choice
Our appreciation of the transcriptional dynamics underlying lineage specification has significantly increased thanks to single-cell RNA sequencing. While epigenetic modifiers play an important role, how they guide this highly dynamic process is still poorly understood. With the support of the Marie Skłodowska-Curie Actions programme, the EpiDevoTimeMachine project will shed light on the role of epigenetic modifiers in establishing cell fate choice. This will have important implications on our understanding of the regulation of mammalian development. Specifically, the project will investigate the combined dynamics and interdependencies of transcription and the polycomb-group of proteins during the differentiation of mouse embryonic stem cells into gastruloids.
Objective
During development, a cell's fate will become increasingly restricted, facilitated by the combined activity of transcription factors and epigenetic modifiers. Single-cell RNA sequencing has greatly improved our appreciation of the transcriptional dynamics underlying lineage specification. However, we still do not fully comprehend how epigenetic modifiers guide this highly dynamic process, as methods that enable us to accurately concatenate a cell's past and present epigenetic state with its current lineage identity are missing.
Here, I propose to investigate the combined dynamics and interdependencies of transcription and the polycomb-group of proteins during the differentiation of mouse embryonic stem cells into gastruloids. First, I aim to deploy a protocol that enables the simultaneous quantification of both layers in the same single cell to disentangle epigenetic from transcriptional heterogeneity. Second, I aim to develop a molecular memory system to record the past epigenetic profiles of single cells. This system will be based on the expression of proteins fused to a bacterial Dcm methylase, which will allow for the timed recording and faithful transmission of historic epigenetic profiles. Combined with quantification of transcription of the same single cell, this will enable us to directly integrate past epigenetic states with the current identity of single cells.
The proposed work here will therefore allow us to directly assess the role of epigenetic modifiers on establishing cell fate choice and will have important implications on our understanding of the regulation of mammalian development.
Fields of science
Keywords
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
1011 JV AMSTERDAM
Netherlands