Chromatin phase separation and nuclear shape fluctuations are correlated in a polymer model of the nucleus

ABSTRACT

Abnormal cell nuclear shapes are hallmarks of diseases, including progeria, muscular dystrophy, and many cancers. Experiments have shown that disruption of heterochromatin and increases in euchromatin lead to nuclear deformations, such as blebs and ruptures. However, the physical mechanisms through which chromatin governs nuclear shape are poorly understood. To investigate how heterochromatin and euchromatin might govern nuclear morphology, we studied chromatin microphase separation in a composite coarse-grained polymer and elastic shell simulation model. By varying chromatin density, heterochromatin composition, and heterochromatin-lamina interactions, we show how the chromatin phase organization may perturb nuclear shape. Increasing chromatin density stabilizes the lamina against large fluctuations. However, increasing heterochromatin levels or heterochromatin-lamina interactions enhances nuclear shape fluctuations by a “wetting”-like interaction. In contrast, fluctuations are insensitive to heterochromatin’s internal structure. Our simulations suggest that peripheral heterochromatin accumulation could perturb nuclear morphology, while nuclear shape stabilization likely occurs through mechanisms other than chromatin microphase organization.

KEYWORDS:

• Blebs
• heterochromatin
• liquid-liquid
• morphology
• nuclear rigidity

Acknowledgments

We thank Martin Falk for instructive discussions. EJB thanks Andrew Stephens and John F. Marko for helpful discussions.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Contribution statement

AE conceptualized the design, AE and AGA generated and analyzed the data, AE, AGA, EJB, and JP analyzed and interpreted the data and wrote the article.

Data availability statement

All codes, structure files, and input parameters are available online under at https://github.com/agattar/Attar_ElasticShellModel.git.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19491034.2024.2351957.

Additional information

Funding

EJB acknowledges support from the NIH Common Fund 4D Nucleome Program [UM1HG011536]. This research is supported by the National Science Center, Poland [Grant Polonez Bis No.~2021/43/P/ST3/01833] and TUBITAK, The Scientific and Technological Research Council of Turkey [1001 Grant No. 122F309].