Statistical mechanics of chromosomes:in vivoandin silicoapproaches reveal high-level organization and structure arise exclusively through mechanical feedback between loop extruders and chromatin substrate properties

Abstract

The revolution in understanding higher order chromosome dynamics and organization derives from treating the chromosome as a chain polymer and adapting appropriate polymer-based physical principles. Using basic principles, such as entropic fluctuations and timescales of relaxation of Rouse polymer chains, one can recapitulate the dominant features of chromatin motion observed in vivo. An emerging challenge is to relate the mechanical properties of chromatin to more nuanced organizational principles such as ubiquitous DNA loops. Toward this goal, we introduce a real-time numerical simulation model of a long chain polymer in the presence of histones and condensin, encoding physical principles of chromosome dynamics with coupled histone and condensin sources of transient loop generation. An exact experimental correlate of the model was obtained through analysis of a model-matching fluorescently labeled circular chromosome in live yeast cells. We show that experimentally observed chromosome compaction and variance in compaction are reproduced only with tandem interactions between histone and condensin, not from either individually. The hierarchical loop structures that emerge upon incorporation of histone and condensin activities significantly impact the dynamic and structural properties of chromatin. Moreover, simulations reveal that tandem condensin–histone activity is responsible for higher order chromosomal structures, including recently observed Z-loops.

Diffusion and distal linkages govern interchromosomal dynamics during meiotic prophase

“…ranging from seconds to minutes). More detailed molecular models provide additional information regarding local structure dynamics and have addressed chromosomal features including loop extrusion and heterogeneous properties (74), centromere tethering (75), and chromosomal crosslinking (76). Our approach complements these detailed models by predicting large-scale chromosomal dynamics and including influences from some of these detailed effects.…”

Mechanisms of DNA Mobilization and Sequestration

“…The most extreme case of histone regulation is the degradation of histone protein following DNA damage, as a driver of increased chromatin motility [ 82 , 83 ]. To better understand the consequences of histone depletion from the perspective of the DNA chain, we have introduced histones and their dynamic turnover into the fluctuating bead–spring chains [ 57 , 84 ]. Using in vivo and in silico approaches we found that both histones and condensin cross-linkers were required in silico in order to quantitatively match the dynamic chromatin compaction observed in vivo [ 57 ].…”

“…To better understand the consequences of histone depletion from the perspective of the DNA chain, we have introduced histones and their dynamic turnover into the fluctuating bead–spring chains [ 57 , 84 ]. Using in vivo and in silico approaches we found that both histones and condensin cross-linkers were required in silico in order to quantitatively match the dynamic chromatin compaction observed in vivo [ 57 ]. An exact experimental correlate of our bead–spring simulation was obtained through analysis of a model-matching, fluorescently labeled, circular chromosome in live yeast cells.…”

“…Second is the mechanical coupling between condensin function and tension on the bead–spring chain. High regions of tension on the chain restrict the loop-extrusion activity of condensin, forcing condensin to idle in place [ 57 ]. Condensin drives fluctuations by actively extruding loops along the chromosome in segments of low tension.…”

“…These non-monotonic relationships are characteristic of polymer networks and their regulation (through L p , cross-linkers, etc.) [ 57 ]. Recruiting cohesin to the site of DNA damage releases DNA from a cluster/node, resulting in increased motion.…”