Computational and experimental analyses of mitotic chromosome formation pathways in fission yeast

Abstract

Underlying higher order chromatin organization are Structural Maintenance of Chromosomes (SMC) complexes, large protein rings that entrap DNA. The molecular mechanism by which SMC complexes organize chromatin is as yet incompletely understood. Two prominent models posit that SMC complexes actively extrude DNA loops (loop extrusion), or that they sequentially entrap two DNAs that come into proximity by Brownian motion (diffusion capture). To explore the implications of these two mechanisms, we perform biophysical simulations of a 3.76 Mb-long chromatin chain, the size of the long S. pombe chromosome I left arm. On it, the SMC complex condensin is modeled to perform loop extrusion or diffusion capture. We then compare computational to experimental observations of mitotic chromosome formation. Both loop extrusion and diffusion capture can result in native-like contact probability distributions. In addition, the diffusion capture model more readily recapitulates mitotic chromosome axis shortening and chromatin density enrichment. Diffusion capture can also explain why mitotic chromatin shows reduced, as well as more anisotropic, movements, features that lack support from loop extrusion. The condensin distribution within mitotic chromosomes, visualized by stochastic optical reconstruction microscopy (STORM), shows clustering predicted from diffusion capture. Our results inform the evaluation of current models of mitotic chromosome formation.

Fission yeast condensin contributes to interphase chromatin organization and prevents transcription-coupled DNA damage

“…The dynamical evolution of the chromosome chain is simulated by integrating the overdamped Langevin equation using a Euler integration method. The full mathematical description of the model is found in [70].…”

A Brownian ratchet model for DNA loop extrusion by the cohesin complex

“…However, DNA extrusion is not the only explanation for chromosome loop formation. Alternatively, cohesin and condensin could generate loops by sequentially topologically embracing two DNAs that come into proximity by Brownian motion, a mechanism that we refer to as diffusion capture ( Cheng et al, 2015; Gerguri et al, 2021 ). Interactions between more than one cohesin binding site in the diffusion capture model could also arise from bridging-induced phase separation ( Ryu et al, 2020a ).…”