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Revealing novel molecular mechanisms linking DNA replication and cell fate decisions

Description du projet

Comprendre ce qui pousse les cellules à changer d’identité

Nos cellules portent le code de toutes les protéines produites par notre corps. Toutefois, chaque type de cellule ne produit que les protéines nécessaires à son fonctionnement. Durant les processus normaux ou anormaux de développement, comme le cancer, une cellule change son identité durant la division cellulaire. À ce moment-là, la chromatine se condense, des copies du code sont effectuées, et elles sont transmises aux cellules filles. La fenêtre entre la condensation et la réorganisation de la chromatine représente une opportunité importante de reprogrammation. Le projet RepDiff envisage de comparer les protéines des cellules indifférenciées, qui restent pluripotentes après la division cellulaire, avec celles présentes dans les cellules qui prennent une nouvelle identité. Ces informations auront un impact important sur les transitions normales et anormales du destin des cellules.

Objectif

All cells in our body share the same genetic information. Cellular identity is determined by epigenetic mechanisms, which control gene expression. Replicating cells should accurately replicate their DNA sequence and copy their epigenetic profile to maintain their identity. DNA replication entails the disruption of the chromatin organization ahead of the replication fork and its restoration behind it. When cells change their identity in either normal development or abnormal processes as cancer, they undergo epigenetic reconfiguration, which defines their new identity.
Recent works have revealed a time gap between DNA replication and epigenetic state restoration of many chromatin regulation layers. I hypothesize that the time until chromatin restoration post DNA replication provides a ‘window of opportunity’ for transcription factors and chromatin regulators to bind otherwise inaccessible areas and to facilitate chromatin reconfiguration and that pluripotent cells have specialized chromatin replication proteins, which preserve their high epigenetic plasticity. To test this hypothesis, I will join the lab of Prof. Anja Groth, a leading expert in the mechanisms controlling chromatin replication. Together with my expertise in stem cells and reprogramming, I will address this question with two sequential steps. I will use a cutting edge, quantitative proteomics method in which nascent DNA is affinity purified and its associated proteins are analyzed by mass-spectrometry (NCC-SILAC). I will use this discovery tool to define the proteins dynamically associated with nascent chromatin in pluripotent cells and cells that undergo cell fate transitions. I will then investigate proteins predicted to effect chromatin restoration/reconfiguration to dissect their functional role. This work has the potential to reveal a mechanistic link between DNA replication and cell fate decision and thus significantly contribute to the fields of development, stem cells, and cancer.

Champ scientifique

CORDIS classe les projets avec EuroSciVoc, une taxonomie multilingue des domaines scientifiques, grâce à un processus semi-automatique basé sur des techniques TLN.

Régime de financement

MSCA-IF-EF-ST - Standard EF

Coordinateur

KOBENHAVNS UNIVERSITET
Contribution nette de l'UE
€ 219 312,00
Adresse
NORREGADE 10
1165 Kobenhavn
Danemark

Voir sur la carte

Région
Danmark Hovedstaden Byen København
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
€ 219 312,00