Differential Crosslinking and Contractile Motors Drive Nuclear Chromatin Compaction

TL;DR

This study models nuclear chromatin organization, revealing how differential crosslinking and contractile motors contribute to heterochromatin compaction and nuclear stiffness, aligning with experimental observations.

Contribution

It introduces a biophysical model demonstrating the roles of crosslink distribution and contractile motors in nuclear chromatin compartmentalization.

Findings

Radial crosslink density influences chromatin segregation.

Contractile motors promote heterochromatin formation at the periphery.

Increased nuclear stiffness correlates with heterochromatin compaction.

Abstract

During interphase, a typical cell nucleus features spatial compartmentalization of transcriptionally active euchromatin and repressed heterochromatin domains. In conventional nuclear organization, euchromatin predominantly occupies the nuclear interior, while heterochromatin, which is approximately 50% more dense than euchromatin, is positioned near the nuclear periphery. Peripheral chromatin organization can be further modulated by the nuclear lamina, which is itself a deformable structure. While a number of biophysical mechanisms for compartmentalization within rigid nuclei have been explored, we study a chromatin model consisting of an active, crosslinked polymer tethered to a deformable, polymeric lamina shell. Contractile motors, the deformability of the shell, and the spatial distribution of crosslinks all play pivotal roles in this compartmentalization. We find that a radial crosslink density distribution, even with a small linear differential of higher crosslinking density at the edge of the nucleus, combined with contractile motor activity, drives genomic segregation, in agreement with experimental observations. This arises from contractile motors preferentially drawing crosslinks into their vicinity at the nuclear periphery, forming high-density domains that promote heterochromatin formation. We also find an increased stiffness of nuclear wrinkles given the preferential heterochromatin compaction below the lamina shell, which is consistent with instantaneous nuclear stiffening under applied nanoindentation. We conclude with the potential for experimental validation of our model predictions.