In vivo, chromatin is a fluctuating polymer chain at equilibrium constrained by internal friction

Abstract

Chromosome mechanical properties determine DNA folding and dynamics, and underlie all major nuclear functions. Here we combine modeling and real-time motion tracking experiments to infer the physical parameters describing chromatin fibers. In vitro, motion of nucleosome arrays can be accurately modeled by assuming a Kuhn length of 35-55 nm. In vivo, the amplitude of chromosome fluctuations is drastically reduced, and depends on transcription. Transcription activation increases chromatin dynamics only if it involves gene relocalization, while global transcriptional inhibition augments the fluctuations, yet without relocalization. Chromatin fiber motion is accounted for by a model of equilibrium fluctuations of a polymer chain, in which random contacts along the chromosome contour induce an excess of internal friction. Simulations that reproduce chromosome conformation capture and imaging data corroborate this hypothesis. This model unravels the transient nature of chromosome contacts, characterized by a life time of ~2 seconds and a free energy of formation of ~1 k B T.. CC-BY 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/192765 doi: bioRxiv preprint first posted online Sep. 24, 2017; Physics of chromosome folding drives and responds to all genomic transactions. In cycling budding yeast cells, large-scale organization of chromosomes in a Rabl-like conformation has been established by imaging and molecular biology approaches (1-4). Yet, the structure of the chromatin fiber at smaller length scales remains more controversial (5). For instance, the recurrent detection of irregular 10-nm fibers by cryo-TEM of thin nuclear sections is questioning the relevance of solenoid or helicoid models of nucleosome arrays (6)(7)(8). This problem has not been clarified by probing the motion of chromosomes in vivo, although dynamic measurements offer a unique opportunity to infer structural properties of genome organization (9). Indeed, we and others have shown that chromosome dynamics in yeast is characterized by sub-diffusive behavior detected by a non-linear temporal variation of the mean square displacement (MSD) of chromosome loci (10-16):( ) = Γwith , , and t the anomaly exponent, amplitude, and time interval, respectively. A subdiffusive response was detected over a broad temporal time scale covering four time decades with an anomaly exponent in the range 0.4-0.6. This response appeared to be consistent with the Rouse model, a generic polymer model that describes chromosomes as a series of beads connected by elastic springs. The length of the springs is related to the mechanical properties of chromatin fiber, namely equal to twice its persistence length (hereafter denoted as the Kuhn length b). The link between the flexibility and the amplitude of the MSD (17) suggested that chromosomes are highly flexible in yeast with b of 1-5 nm (10). Inconsistent with structural and mechanical mode...

Polymer coil-globule phase transition is a universal folding principle of Drosophila epigenetic domains

“…It is therefore tempting to link the coil-globule transition of chromosomes to the vanishing of the second virial coefficient of nucleosome-nucleosome interaction. This is also in line with quite recent measurements of chromosome dynamics in yeast, which has been modeled as a Rouse dynamics slowed down by nucleosomenucleosome transient interactions [29]. Following this line and going into more detail, inactive (black ) chromatin is very close to the Θ-point, indicating that nucleosomenucleosome interactions might be dominant within inactive domains.…”

“…First, color -specific measures of the Kuhn length (in base pairs and in nanometers) of active, inactive and repressed domains respectively. Strikingly, these measures are on par with Hi-C data in mammals [34] as well as to most recent dynamic measurements in yeast [29]. The knowledge of both Kuhn lengths leads to the value of the compaction of the chromatin, i.e.…”

“…To end, it may be useful to point out here that the regular and somehow rigid nucleosome arrays of Figures 3D and 4 should only be intended as indicative representations of average organizations: the actual nucleosome orientation depends of course on precise architectural parameters that display inhomogeneities along the genome [27,28], and are, moreover, dynamically fluctuating [29][30][31]. Note also that the two-angle model is used here only to check the plausibility of physical parameters that are obtained in a completely independent way by means of a much more coarse grained model, i.e.…”

Telomeric chromosome ends are highly mobile and behave like free double-strand DNA breaks

“…We observed that the coefficient of diffusion of the trnascriptionaly activated HXK1 gene decreases independently of its interaction with the nuclear periphery. This is reminiscent of the confined motion of mRNA-producing genes observed in human cells 70 and agrees with the increased chromatin dynamics observed upon transcription arrest 71 . Transcriptional activation and the action of nucleosome remodelers have in other instances been shown to increase chromatin diffusion coefficient in yeast 72 .…”

Formation of correlated chromatin domains at nanoscale dynamic resolution during transcription

“…In the absence of transcriptional activity, chromatin movements were no longer correlated independently of their constant, but small correlation length. Because protein and mRNA concentration as well as transient contacts and looping change during transcription, they also affect the mechanical properties of the chromatin fiber (20,44,45).…”