Inferring the physical properties of yeast chromatin through Bayesian analysis of whole nucleus simulations

Abstract

BackgroundThe structure and mechanical properties of chromatin impact DNA functions and nuclear architecture but remain poorly understood. In budding yeast, a simple polymer model with minimal sequence-specific constraints and a small number of structural parameters can explain diverse experimental data on nuclear architecture. However, how assumed chromatin properties affect model predictions was not previously systematically investigated.ResultsWe used hundreds of dynamic chromosome simulations and Bayesian inference to determine chromatin properties consistent with an extensive dataset that includes hundreds of measurements from imaging in fixed and live cells and two Hi-C studies. We place new constraints on average chromatin fiber properties, narrowing down the chromatin compaction to ~53–65 bp/nm and persistence length to ~52–85 nm. These constraints argue against a 20–30 nm fiber as the exclusive chromatin structure in the genome. Our best model provides a much better match to experimental measurements of nuclear architecture and also recapitulates chromatin dynamics measured on multiple loci over long timescales.ConclusionThis work substantially improves our understanding of yeast chromatin mechanics and chromosome architecture and provides a new analytic framework to infer chromosome properties in other organisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1199-x) contains supplementary material, which is available to authorized users.

Chromatin stiffening underlies enhanced locus mobility after DNA damage in budding yeast

“…We plotted the mean square distances as a function of genomic separation between the loci in Fig C, as previously shown in Arbona et al (). For the 12 pairs of loci located far from the centromere (involving loci R2, R3, or R4), increased similarly and roughly linearly with genomic separation s (Fig C).…”

“…This indicates a pronounced stretching of the chromatin fiber in the centromeric region relative to the rest of the chromosome. While the ideal chain model cannot readily explain this observation, pericentromeric stretching can be recapitulated by a polymer model that accounts for nuclear confinement, tethering of centromeres to the spindle pole body (SPB), as well as topological and steric constraints among chromosomes (Wong et al , , ; Arbona et al , ). These effects result in entropic repulsion between chromosome arms, as in a polymer brush or star shaped polymer (De Gennes, ; Zimmer & Fabre, ; Daoud & Cotton, ), which leads to increased elongation away from the spindle pole.…”

“…In order to understand the mechanistic links between increased intrachromosomal distances and enhanced chromatin mobility upon DSBs, we turned to computational simulations of yeast chromosomes (Wong et al , , ; Arbona et al , ). In our simulations, chromosomes are defined by their known genomic lengths, an assumed constant compaction C , and persistence length P , the centromeres are tethered to the SPB using a spring‐like link of equilibrium length L , and the telomeres are tethered to the nuclear envelope using a short‐range attractive force.…”

“…At the molecular level, it was shown that chromatin dynamics can be enhanced both locally and globally by activating the DNA damage response (DDR) without inducing actual DNA damage (Bonilla et al , ; Seeber et al , ). On the other hand, recent work has made clear that the spatial architecture and dynamics of yeast chromosomes can be well understood from the random motions of semiflexible polymer chains tethered at the centromeres and telomeres (Tjong et al , ; Wong et al , , ; Albert et al , ; Hajjoul et al , ; Avşaroğlu et al , ; Rosa & Zimmer, ; Vasquez & Bloom, ; Imakaev et al , ; Chiariello et al , ; Arbona et al , ). This suggests at least two very distinct mechanisms by which the DDR might affect chromatin mobility: (i) a perturbation of constraints extrinsic to the chromatin fiber, namely tethering at the centromere, at the telomeres or both, or (ii) an alteration in the intrinsic mechanical properties that determine the dynamics of the chromatin polymer, notably chromatin compaction and rigidity.…”

DNA Repair: The Search for Homology

“…This depletion requires ATR Mec1 -mediated damage signaling and the INO80 chromatin remodeler. The loss is not simply around the site of damage but global, and appears to cause a general decondensation of yeast chromatin (though yeast don’t have much higher-order chromatin beyond an 11 nm fiber) [86, 87]. Damage-provoked histone loss (or artificial histone depletion) was suggested to create increased fiber flexibility, which seems to be the opposite of the conclusion reached by Fabre and Zimmer [63] that damage leads to chromatin stiffening.…”