Dynamic asymmetry and why chromatin defies simple physical definitions

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Abstract

Recent experiments have demonstrated a nucleus where chromatin is molded into stable, interwoven loops. Yet, many of the proteins, which shape chromatin structure, bind only transiently. In those brief encounters, these dynamic proteins temporarily crosslink chromatin loops. While, on the average, individual crosslinks do not persist, in the aggregate, they are sufficient to create and maintain stable chromatin domains. Owing to the asymmetry in size and speed of molecules involved, this type of organization imparts unique biophysical properties—the slow (chromatin) component can exhibit gel-like behaviors, whereas the fast (protein) component allows domains to respond with liquid-like characteristics.

Introduction

The eukaryotic nucleus is a wild tangle of protein and nucleic acid, overflowing in activity. However, despite its chaotic appearance, the business of the nucleus is readily accomplished. In part, this is achieved by dynamically organizing chromatin into domains that possess distinct biophysical properties, enable specific biochemical activities, and have the versatility to change throughout development and in response to the environment. Here, I discuss some new insights into the physical consequences of dynamic chromatin organization.

Section snippets

Chromatin organization

In essence, chromatin is DNA wrapped around histone proteins [1]. But, there is also a host of other proteins and RNA associated with chromatin that can be considered integral to the chromatin ultrastructure [2, 3, 4]. However, unlike DNA and histones, most chromatin-associated proteins are incredibly dynamic, perhaps bound only transiently to any other molecules comprised within the chromatin fiber [5, 6, 7]. Remarkably, these dynamic proteins establish and maintain a stable, reproducible

Chromatin phase separation

Formally, the question of whether chromatin is organized into phase-separated domains is somewhat ill-posed. Undoubtedly, distinct regions of chromatin fibers exist in separate nuclear compartments, but by virtue of being—at least in principle—a single entity, it is probably inappropriate to refer to different regions of a continuous polymer as phase separated from itself. However, a single chromatin fiber may traverse and/or induce the formation of several distinct phase-separated domains as

Viscoelastic phase separation of HP1α-DNA condensates

The most straightforward example of a chromatin domain is constitutive heterochromatin. This type of chromatin is characterized by a dense appearance that preferentially localizes to the nuclear periphery and is bound by members of the Heterochromatin Protein 1 (HP1) family [11,12,62]. In mammals, HP1α is critical for condensing and positioning heterochromatin [63,64]. Recently, it was shown that HP1α undergoes phase separation when it is phosphorylated or mixed with DNA [34,65]. Furthermore,

Consequences of viscoelastic phase separation and dynamic asymmetry

What conclusions or insights can be taken away from conceptualizing chromatin as we have here: a polymer gel embedded in proteinaceous liquid that collectively behaves viscoelastically? First of all, it is worth noting that many of the advantages of LLPS are still true of these condensates, such as concentrating effects, self-assembly, and curated local environments [43,44]. However, in contrast to liquids, a viscoelastic material can respond in opposition to mechanical stresses (Figure 3).

Conflict of interest statement

The authors declare no conflict of interests.

Acknowledgements

Support to SR through the UCSF Program for Breakthrough Biomedical Research (PBBR) and Sandler Foundation.

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