Heterogeneous fluid-like movements of chromatin and their implications to transcription

Abstract

Eukaryotic chromatin is a complex of genome DNA and associated proteins, and its structure and dynamics play a crucial role in regulating DNA functions. Chromatin takes rather irregular structures in the nucleus and exhibits heterogeneous sub-diffusive movements as polymers fluctuating in a fluid state. Using genome-wide single-nucleosome tracking data, heterogeneity of movements was statistically analyzed, which categorized chromatin into two types: slow chromatin that moves under structurally constrained environments and fast chromatin that moves with less constraints. Interactions of chromatin to various protein factors determine the motional constraints. For example, loss of the cohesin complex that bundles the chromatin chains reduces the motional constraints and increases the population of fast chromatin. Another example is the transcriptional machinery. While it was previously thought that the transcriptional activity is associated with more open and dynamic chromatin structure, recent studies suggested a more nuanced role of transcription in chromatin dynamics: dynamic association/dissociation of active RNA polymerase II (RNAPII) and other transcription factors and Mediators (TF-Meds) transiently bridges transcriptionally active DNA regions, which forms a loose network of chromatin and constrains chromatin movement, enhancing the slow chromatin population. This new view on the dynamical effects of transcription urges a reflection on the traditional model of transcription factories and invites the more recent models of condensates/phase-separated liquid droplets of RNAPII, transcription factors, and Mediators. The combined procedure of genome-wide single-nucleosome tracking and its statistical analysis would unveil heterogeneity in the chromatin movement, which should provide a key to understanding the relations among chromatin dynamics, structure, and function.

The solid and liquid states of chromatin

“…Rapid local chromatin movements has also been obtained by combining confocal microscopy of fluorescently labeled bulk histones or DNA binding fluorophores with displacement correlation analysis [ 182 , 186 ]. Finally, statistical analyses [ 187 , 188 ] of genome-wide single nucleosome tracking data [ 133 ] have demonstrated that the genomic nucleosomes show fluid-like behavior at the 300-nm length scale. Taken together, these studies demonstrate that chromatin locally is not a rigid solid and has some dynamic features that are suggestive of liquid-like properties.…”

Regulation of Nuclear Mechanics and the Impact on DNA Damage

“…These networks have not only been associated with phase separation events but also with the formation of transient chromatin bridges [ 88 ]. Interestingly, whilst active chromatin regions are usually associated with open and dynamic conformations, recent reports challenge this view by showing that the bridging effect of RNAPII and associated transcription machinery can increase chromatin constraints, reduce chromatin mobility and possibly affect local stiffness [ 89 , 90 ].…”

“…Both disruption of nuclear actin polymerisation and MVI force-sensing—through the introduction of an MVI spring mutant that changes its response to force—abrogate RNAPII distribution and have severe consequences for gene expression using RNA-Seq [ 34 ]. The role of MVI in regulating RNAPII clustering also suggests a role for this molecular motor in RNAPII-dependent chromatin bridging and droplet formation [ 89 , 90 ], thus leading to local changes to chromatin mechanics.…”

CENP-A nucleosome—a chromatin-embedded pedestal for the centromere: lessons learned from structural biology

“…Actually, recent efforts to visualize chromatin in cells using cryo-electron tomography (cryo-ET) and related techniques [ 118 , 119 ] are supporting a dynamic fluid-like organization of chromatin [ 120 ] rather than the rigid 30-nm chromatin fiber model based on in vitro chromatin studies that was widely accepted for decades. Comprehensive chromatin models based on an array of biophysical studies propose chromatin to be organized in distinct domains that have irregular fluid-like nucleosome organization [ 121 ].…”