Spatio-temporal Organization and Expression of the Genome

Informazioni relative al progetto

4D-GenEx

ID dell’accordo di sovvenzione: 757956

DOI

10.3030/757956

Progetto chiuso

Data della firma CE 25 Settembre 2017

Data di avvio 1 Aprile 2018

Data di completamento 31 Marzo 2025

Finanziato da

• EXCELLENT SCIENCE - European Research Council (ERC)

Costo totale

€ 1 499 750,00

Contributo UE

€ 1 499 750,00

Coordinato da

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Periodic Reporting for period 5 - 4D-GenEx (Spatio-temporal Organization and Expression of the Genome)

Periodo di rendicontazione: 2024-04-01 al 2025-03-31

Sintesi del contesto e degli obiettivi generali del progetto

Every cell in our body contains the same genome — a vast ensemble of over 20,000 genes packed into long DNA molecules inside the nucleus. Yet different cells activate different subsets of genes, allowing them to perform specialized functions. Disruptions in this tightly regulated process can lead to diseases such as cancer, where a cell may inappropriately express certain genes and become tumorigenic.

Recent discoveries have shown that the way DNA is folded in three-dimensional space inside the nucleus plays a crucial role in determining which genes are turned on or off. In particular, certain DNA elements known as “enhancers” can activate genes that are far away on the linear DNA sequence, brought close together by 3D folding. However, despite a growing number of observations linking genome architecture to gene regulation, the underlying mechanisms remain poorly understood.

The aim of the 4D-GenEx project was to uncover the physical principles that govern how the genome is spatially organized in the nucleus and how this organization influences gene expression. To achieve this, we developed innovative experimental and theoretical tools to visualize and manipulate the 3D genome in living cells, and to model the links between structure, dynamics, mechanics, and gene function.

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

Over the course of the project, we made several key advances:

• We showed how the local folding of DNA into structures known as topologically associating domains (TADs) enables cells to co-regulate multiple genes in a coordinated fashion. This was achieved by developing a microscopy approach to image the transcriptional activity of gene pairs at single-molecule resolution and developing a data analysis framework to quantify how transcription are coupled between gene pairs.
→ This work is presented in our eLife article.

• We developed a novel technique to physically manipulate a specific genomic region within the nucleus using magnetic nanoparticles. By applying controlled forces directly to the genome, we revealed the viscoelastic properties of chromatin and challenged the notion that it behaves like a gel, with direct implication for gene expression.
→ These findings appeared in our Science article.

• We constructed a unified theoretical framework to interpret the structure, dynamics, and mechanical behavior of chromosomes, based on principles of polymer physics. Our analysis demonstrated that existing models fail to reconcile all experimental observations and identified the physical conditions that a successful model must meet.
→ This work was published as a preprint and is currently under review.

• We synthesized and discussed emerging views on interphase chromatin mechanics and genome regulation in a review article in a widely read journal, laying out new conceptual directions for future research.
→ This appeared as a review in Current Opinion in Genetics & Development.

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 4D-GenEx project achieved several breakthroughs beyond the existing state of knowledge:
• We pioneered a method to actively perturb genome organization using live-cell magnetic micromanipulation — a first in the field.
• We developed new analytical frameworks for measuring and interpreting transcriptional co-regulation at the single-allele level.
• We introduced a novel physical theory connecting chromosome structure, dynamics, and mechanics, based on scaling laws and polymer models, opening new avenues for both experimental and theoretical work.

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