Orateur
Description
Centromeres are essential for accurate chromosome segregation, yet their 3D organization remains largely unknown. Holocentric chromosomes distribute centromeric activity along their entire length, while monocentric chromosomes, like those in humans and chickens, localize it to a single region. Despite this morphological difference, both systems rely on conserved biophysical mechanisms, including condensin-mediated loop extrusion and sister chromatid cohesion, to create a functional centromeric structure capable of withstanding spindle forces and enabling proper kinetochore attachment.
To investigate these mechanisms, we employed polymer simulations to model the 3D organization of mitotic holocentric chromosomes, incorporating loop extrusion by condensin and cohesin, nucleosome interactions, and cohesion. Our model predicts a robust architecture consisting of two cohesed chains of consecutively linked condensin-mediated loops. In this conformation, condensins form two peripheral axes that align with kinetochore locations and provide mechanical rigidity, consistent with experimental data in holocentric species.
We then generalized this folding principle to monocentric chromosomes by introducing a gradient of loop sizes and a cohesion gap at the core centromere, where CENP-A nucleosomes reside. This adaptation recreates the exposed bipartite CENP-A structure observed in chicken centromeres, which remains stable under spindle tension.
Notably, both our holocentric and monocentric models remain robust under variations in loop size and partial cohesin depletion.
By integrating polymer simulations with Hi-C data and imaging, we provide a predictive framework to model centromere folding across eukaryotes. It generates testable hypotheses on the effects of cohesin or condensin depletion and offers new insights into the physical basis of centromere function and chromosome missegregation.