CTCF control of genome stability in ageing

Informazioni relative al progetto

CTCFStableGenome

ID dell’accordo di sovvenzione: 788937

DOI

10.3030/788937

Progetto chiuso

Data della firma CE 25 Giugno 2018

Data di avvio 1 Settembre 2019

Data di completamento 31 Agosto 2024

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 2 488 251,00

Contributo UE

€ 2 488 251,00

Coordinato da

DEUTSCHES KREBSFORSCHUNGSZENTRUM HEIDELBERG
Germany

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

Periodo di rendicontazione: 2024-03-01 al 2024-08-31

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

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).

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

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