After an injury, DNA not only alters its activity but also the way it is organized spatially within the cell nucleus. In this process, certain regions of DNA establish new physical contacts through chromatin loops that act as bridges, bringing together sequences that are far apart in the genome’s linear sequence. Now, a study has identified — in an animal model — the formation of these loops as an essential step in tissue regeneration following after an injury.
The study, published in the journal Science Advances, is led by Professor Montserrat Corominas of the Faculty of Biology and the Institute of Biomedicine at the University of Barcelona (IBUB). Also notable is the participation of the team led by Marc Martí-Renom, an ICREA researcher at the National Centre for Genomic Analysis (CNAG) — based at the Barcelona Science Park (PCB-UB) — and at the Centre for Genomic Regulation (CRG), as well as researchers from the University of Lausanne (Switzerland).
The results show that tissue regeneration depends not only on the genes that are switched on or off after an injury, but also on how DNA is reorganized within the cell nucleus. The discovery reveals the three-dimensional architecture of the genome as a new layer of regulation that is essential for regenerative processes.
Unraveling the unknown role of genome architecture
In the cell nucleus, DNA associates with proteins to form a structure known as chromatin, which organizes the genome in eukaryotic cells.
“This chromatin adopts a complex three-dimensional architecture that allows contacts to be established between regions of the genome that are far apart, and regulates which genes are activated or remain inactive at any given moment,” explains Corominas, a member of the UB’s Department of Genetics, Microbiology and Statistics.
However, the evidence suggests that the regenerative potential of affected tissues is closely linked to the dynamics of chromatin state and structure.
In the study, the team used imaginal discs from the wing of the fruit fly Drosophila melanogaster as a model to study regeneration.
“Importantly, we have identified three of these DNA loops and have experimentally demonstrated that they are necessary for efficient regeneration,” notes Carlos Camilleri-Robles (UB-IBUB), one of the lead authors of the article. “When we altered the regions responsible for their formation, the tissues’ regenerative capacity was significantly reduced, while the organism’s normal development remained virtually unaffected.”
“Overall, our results identify a previously unknown role for genome architecture in tissue repair, and reveal an additional layer of regulation of gene expression during regeneration,” concludes Palmira Llorens-Giralt (UB-IBUB), first author of the article.