Description du projet
Le rôle des modificateurs épigénétiques dans la détermination du destin cellulaire
Notre appréciation de la dynamique transcriptionnelle régissant la spécification des lignées s’est considérablement améliorée grâce au séquençage d’ARN unicellulaire. Si les modificateurs épigénétiques jouent un rôle important, la manière dont ils guident ce processus très dynamique restent mal comprise. Fort du soutien du programme Actions Marie Skłodowska-Curie, le projet EpiDevoTimeMachine mettra en lumière le rôle des modificateurs épigénétiques dans la détermination du destin cellulaire. Cette démarche aura des retombées importantes sur notre compréhension de la régulation du développement des mammifères. Le projet étudiera en particulier la dynamique et les interdépendances combinées de la transcription et des protéines du groupe Polycomb pendant la différenciation des cellules souches embryonnaires murines en gastruloïdes.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régime de financement
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinateur
1011 JV AMSTERDAM
Pays-Bas