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Bioinformatics, Computational and Systems Biology

Bioinformatics, Computational and Systems Biology - Poster Session A

Poster A1 - A Model of Mitotic Signaling Across Various Chromosomal Geometries in Eukaryotic Cells

Thursday, October 24, 2024
10:00 AM - 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  The chromosome passenger complex (CPC) is central to a signaling network that coordinates many events during mitosis, including spindle assembly. Many cancers, including breast cancer, show high prevalence of aneuploidy, which arises from dysregulation of mitotic signaling. Using VCell, a spatial modeling software, we simulate a reaction-diffusion model of this network during metaphase to estimate the concentrations of proteins in the network and predict CPC accumulation. The model currently employed is of a metacentric chromosome, which represents human biology but is not fully representative of all possible centromeric positions. To recapitulate the mouse chromosome, we modified the geometry by adjusting the positioning of the kinetochores and used in silico perturbations to test the contributions of two subnetworks of the model in CPC centromeric accumulation.

Materials and

Methods:  Virtual Cell (VCell), a reaction-diffusion modeling software, was used to simulate the behavior of individual chromosomes, with initial conditions derived from experimental measurements. The model includes sixty-two reactions to estimate the accumulation of the chromosomal passenger complex (CPC) and other proteins, using both Michaelis-Menten and mass-action kinetics. A two-way ANOVA was performed to analyze differences between telocentric and metacentric chromosomes, with chromosome sizes fixed at 1.2 by 3.2 micrometers and kinetochore sizes at 0.425 by 0.3 micrometers when relaxed and 0.125 by 0.3 micrometers when tense. Kinetochores were repositioned to the lower boundary for telocentric chromosomes. Reductions in initial conditions were used to simulate haploinsufficiency, and inhibitions were modeled by adjusting initial protein or enzyme concentrations to limit production or impede processes. All results were visualized using heatmaps and line plots in RStudio and Python.

Results, Conclusions, and Discussions: Our study highlights key differences in centromeric signaling between metacentric human chromosomes and telocentric mouse chromosomes. In the telocentric model, we observed greater accumulation of the chromosomal passenger complex (CPC) within the inner centromere compared to the metacentric chromosomes. Haspin knockdown resulted in a higher kinetochore concentration in the telocentric model than in the metacentric model, which correlates with the kinetochore subnetwork within the double-positive feedback loop. Additionally, Plk1 knockdown had a more pronounced effect on the kinetochore subnetwork than on the cohesin subnetwork in the telocentric model. The effects of Sgo1 heterozygosity combined with 50% CPC inhibition were less pronounced in the telocentric model compared to the metacentric model, resulting in a smaller effect on CPC accumulation. However, CPC was unable to accumulate effectively in the inner centromere when Sgo1 heterozygosity and 99% CPC inhibition were applied.This finding better recapitulates experimental results from a Sgo1+/- mouse model showing no effect of CPC inhibition at 50% but a large effect at 99%.

Acknowledgements (Optional):  SASCO: NCI U54 CA274499 Janes Lab & Stukenberg Lab
Systems Bioengineering REU at University of Virginia