Orateur
Description
Inside the cellular nucleus, DNA is compacted into a highly dynamic polymer-like structure known as chromatin. This organization enables the storage of genetic information while still allowing regulated access for processes such as transcription, replication, and repair. The self-organization of chromatin into functional domains, facilitated by a combination of physical interactions and biochemical processes, remains one of the most fundamental and unresolved challenges in molecular biology. Recent studies suggest that chromatin organization is not purely random but rather orchestrated by specialized proteins and molecular motors that dynamically reshape its structure over time.
Our research is centered on modelling the loop extrusion process, a key mechanism thought to drive the formation of topologically associating domains (TADs) and other large-scale chromatin structures. Loop extrusion is mediated by condensin, a complex of proteins that actively translocates along DNA while anchoring and extruding loops. In vitro assays have demonstrated that condensin binds preferentially to free DNA, exhibiting a remarkable ability to extrude loops at rates measurable in real time. However, the in vivo behavior of this mechanism remains less understood, as the chromatin landscape is densely populated with obstacles such as nucleosomes, transcription factors, and other chromatin-associated proteins. These obstacles are believed to influence loop extrusion efficiency and dynamics significantly, but their exact roles are still debated.
To address these questions, we have developed a one-dimensional (1D) computational model that captures the interplay between loop extrusion machinery, nucleosome positioning, and the mechanical properties of the chromatin fiber. This model employs just two tunable parameters, yet it successfully recapitulates key metrics observed experimentally, including loop extrusion processivity and first passage times. By systematically varying these parameters, we aim to disentangle the individual contributions of chromatin-bound obstacles and DNA mechanics to the overall dynamics of loop extrusion.
In addition to quantifying the effects of these factors, our model provides a framework for exploring the emergent properties of loop extrusion under biologically realistic conditions. For example, it predicts how variations in nucleosome density or the presence of sequence-specific DNA-binding proteins can alter the rate and extent of loop formation. The insights gained from this 1D model serve as a foundation for more complex three-dimensional (3D) simulations, which will incorporate higher-order chromatin folding and interactions between multiple extrusion complexes. Such extensions will allow us to compare our findings directly with experimental imaging data and Hi-C contact maps, bridging the gap between theoretical predictions and empirical observations.
Looking forward, the next steps in our work include adapting the model to capture the dynamic interplay between condensin and other architectural proteins, such as cohesin and CTCF, which are known to play complementary roles in chromatin organization. By combining our theoretical approach with high-resolution experimental data, we hope to uncover the principles governing chromatin self-organization and elucidate how disruptions to these processes contribute to disease states such as cancer and developmental disorders.