Propagating DNA Modifications Across the Cell Cycle

Informations projet

DNAmod_PROPAGATION

N° de convention de subvention: 747332

DOI

10.3030/747332

Projet clôturé

Date de signature de la CE 14 Mars 2017

Date de début 1 Septembre 2018

Date de fin 2 Mars 2021

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 212 194,80

Contribution de l’UE

€ 212 194,80

Coordonné par

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 1 - DNAmod_PROPAGATION (Propagating DNA Modifications Across the Cell Cycle)

Période du rapport: 2018-09-01 au 2020-08-31

Résumé du contexte et des objectifs généraux du projet

DNA in cells is decorated with methyl and hydroxymethyl marks, which are required for the cell to function. When cells divide, DNA replication dilutes these marks. After replication, these marks must therefore be re-established on DNA. Large regions of the genome commonly lose their DNA methylation in both cancerous and ageing cells. Both cancerous and ageing cells have undergone many cell divisions. This loss may therefore be linked to DNA replication and cell division.

How long it takes to re-establish these marks after DNA replication, and in what manner this happens, is unclear, because the technology required has been unavailable. In this project, I sought to develop new methods capable of addressing these questions and profile how these marks return to their normal levels after being diluted by DNA replication. The novel methods developed in this project can be applied to diverse models to deepen our understanding of DNA modifications in disease states. This work, though not yet finalized, indicates that the rate of cell division outpaces re-establishment of DNA modifications, consistent with the loss of methylation seen after numerous cell divisions in both cancer and ageing. These novel technologies have provided new insights into the links between DNA methylation, DNA replication, and the cell cycle.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

I have established a new, robust method to measure DNA methylation and hydroxymethylation levels in mammalian stem cells. This was interdisciplinary work that also included establishment of advanced data analysis pipelines. This work has uncovered new, soon-to-be-published insights into the dynamics of DNA modifications in these cells that now provide new models and tools for both the DNA replication and epigenetics fields. Publication of this work will ensure widespread dissemination of the method across the broader scientific community.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The methods developed in this project, and its findings to date, push forward the state-of-the-art in the fields of epigenetics and DNA replication. These tools will expand our basic knowledge of how these fundamental aspects of cell biology are linked, as well as facilitate future studies of the mechanistic basis for DNA methylation loss in ageing and disease. It also provides new insights into the relatively less-studied DNA hydroxymethyl mark, and characterizes its maintenance in dividing cells.

msca-summarypub.png