Biological Physics and Bioinformatics Seminar

https://zoom.us/j/91976153012?pwd=azNiMWE4UnhPN3lRQlY2UHZHOXVkQT09
Meeting ID: 919 7615 3012
Passcode: 747922
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Bogdan Lesyng (UW)
Anna Niedźwiecka (IF PAN)
Piotr Zielenkiewicz (IBB)

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Abstract
Loop extrusion is a model that aims to describe the process by which chromatin loops are formed and maintained within the three-dimensional (3D) structure of the genome. This model is particularly relevant for understanding the organization and function of Topologically Associating Domains (TADs), which are self-interacting genomic regions that have been implicated in gene regulation, chromatin organization, and other nuclear processes. The loop extrusion model provides a theoretical framework to explain how chromatin loops are dynamically formed, stabilized, and disassembled, as well as the role of key protein factors such as cohesin and CTCF in this process.
According to the loop extrusion model, chromatin loops are generated by the action of a molecular complex called the extrusion complex, composed of the ring-shaped cohesin protein and other associated factors. The extrusion complex is loaded onto the chromatin fiber and starts to extrude the chromatin by translocating along the DNA, progressively enlarging the loop. As the extrusion complex moves, it brings together distant genomic regions, thereby facilitating their spatial proximity and interactions.
The loop extrusion process continues until the extrusion complex encounters a boundary element, often formed by the binding of the CCCTC-binding factor (CTCF) protein to specific DNA sequences. CTCF acts as a barrier or insulator, preventing the extrusion complex from progressing further and defining the borders of TADs. This leads to the formation of stable chromatin loops, which can bring together regulatory elements such as enhancers and promoters, thus influencing gene expression.
Loop extrusion modeling has several important implications for our understanding of genome organization and function:
1. Formation and stabilization of TADs: The loop extrusion model provides a mechanistic explanation for the formation and stabilization of TADs, which are essential for maintaining proper chromatin organization and ensuring accurate gene regulation.
2. Dynamic nature of chromatin loops: Loop extrusion emphasizes the dynamic nature of chromatin loop formation and disassembly, which is crucial for understanding how the 3D genome structure adapts to different cellular contexts and changes during development.
3. Role of cohesin and CTCF: The model highlights the critical role of cohesin and CTCF proteins in shaping the 3D genome structure by mediating loop extrusion and defining TAD boundaries, respectively.
4. Implications for gene regulation: Loop extrusion can bring together distant genomic regions, such as enhancers and promoters, facilitating their interaction and potentially influencing gene expression.
5. Relevance for disease: Disruptions in the loop extrusion process or the factors involved may contribute to various diseases, including developmental disorders and cancer, by affecting chromatin organization and gene regulation.
6. Artificial Intelligence: our comprehensive approach combining machine learning models, polymer biophysical simulations, and experimental 3D genomics methods provides a powerful tool for studying human genome topology at the single chromatin loop scale. It has enabled us to gain new insights into the relationship between DNA sequence, structure, and function, with important implications for understanding disease development and potential therapeutic interventions.
In summary, loop extrusion modeling provides a comprehensive framework for understanding the formation and maintenance of chromatin loops and their role in the 3D organization of the genome. This model has important implications for gene regulation, genome function, and the molecular basis of various diseases.