Propagating DNA Modifications Across the Cell Cycle

Project Information

DNAmod_PROPAGATION

Grant agreement ID: 747332

DOI

10.3030/747332

Project closed

EC signature date 14 March 2017

Start date 1 September 2018

End date 2 March 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 212 194,80

EU contribution

€ 212 194,80

Coordinated by

KOBENHAVNS UNIVERSITET
Denmark

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

Reporting period: 2018-09-01 to 2020-08-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.

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