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.

Current Pathophysiological and Therapeutic Options for Children with Hutchinson Gilford Syndrome

“…The most striking feature is the premature ageing of affected children . "From cellular aspect, different features of aging have been described, instability of genome, telomere lengths changes, epigenetic impairment, disturbances in proteostasis, senescence of cells, disturbances of mitochondrial functions, changes in intercellular communication, stem cell depletion and deregulated nutrient sensing" [3,24,72]. "One cause of progeria is a dominant de novo mutation within exon 11 of codon 608 on chromosome 1q22 on the LMNA gene, which induces the synthesis of progerin, a mutant form of lamin A" (4,5,7).…”