CTCF control of genome stability in ageing

Informations projet

CTCFStableGenome

N° de convention de subvention: 788937

DOI

10.3030/788937

Projet clôturé

Date de signature de la CE 25 Juin 2018

Date de début 1 Septembre 2019

Date de fin 31 Août 2024

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 2 488 251,00

Contribution de l’UE

€ 2 488 251,00

Coordonné par

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany

Periodic Reporting for period 4 - CTCFStableGenome (CTCF control of genome stability in ageing)

Période du rapport: 2024-03-01 au 2024-08-31

Résumé du contexte et des objectifs généraux du projet

My ERC Advanced Grant supports my lab in trying to understand what mechanisms shape mutagenesis. In other words, why our DNA becomes damaged during our lives. In particular, we focus on how a specific protein called CTCF binds to the genome, and what this binding means for our genetic material. One possible thing that is happening is that the protein's DNA contacts change the sensitivity (either up or down) to DNA damaging agents.

This is important for society, because DNA damage is one of the leading causes of cancer, including skin cancer from sun exposure and liver cancer from toxins in our food. How this DNA damage becomes fixed into mutations is a poorly understood area that my laboratory is attempting to address.

We will be looking at this from both a classical approach of tuning the amount of both the CTCF protein and the proteins that define cell type programs up and down in isolation and in combination, using liver cells as a model system. In addition, we will be directly exposing these cells to chemical carcinogens similar to those found in certain highly processed meats, in order to explore how the changes in protein-DNA contacts re-shapes mutations in the genome.

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

The first major set of discoveries in this project reports how the chemical carcinogen used in this grant creates mutations genome-wide (Aitken et al Nature 2020). This study was important because, although many human studies have published human cancer genomes, human cancer genomes are not controlled experiments. In contrast, our work used inbred mice and a highly controlled cancer induction, which in effect re-ran the cancer genome's evolution hundreds of times to see what commonalities emerged. We discovered a mechanism called lesion segregation, that explains how the DNA damage gradually resolves into fixed mutations in the genome. This was followed up in a number of important publications, including two highest impact papers dissecting the single-strand and single-mitosis influences on mutagenesis (Anderson et al Nature 2024; Ginno et al Nature Genetics 2024, respectively). We have also carefully identifed the functional impact on polymerases of DNA damage (Nicholson et al PNAS 2024).

The second focus I would like to showcase looked, in part, at how CTCF binding evolves between species (Azazi et al, BMC Biology 2020; Rimoldi et al Genome Biology 2024), and how changes in CTCF occupancy or dosage can connect to genome re-organization (Yin et al J Hepatology 2024).

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 lesion segregation papers, in particular, represent a totally novel approach to understanding the cancer genome. Our follow up work has also performed the first comparative study that connects liver master regulator binding, CTCF binding, and cancer evolution, and is currently being submitted for publication. The mechanism of lesion segregation appears to be active in human tumours, including genomes within the International Cancer Genome Consortium's datasets. These human cancers had never been inspected with an eye to looking for asymmetric mutations, which are the hallmark of lesion segregation. Once we knew about this mechanism, the prevalence of this mechanism in human tumours became addressable.

By the end of the project, we have completed our work on understanding how CTCF binding and liver master regulators and their enhancers shape the mutational landscape of the genome, by exploiting different species of mice. This was in part a replacement strategy driven by the coronavirus pandemic, because our mouse house's ability to generate the collection of mouse variations we initially planned on was severely constrained. This strategy was discussed with an ERC Program officer and agreed in principle.

Graphical display of main project goal