Interplay of epigenetic regulation and chromatin-lamina interaction modulates the morphology of lamina-associated domains.

Abstract

In eukaryotic nuclei, a significant portion of transcriptionally repressed chromatin is anchored to the nuclear lamina (NL), leading to the formation of lamina-associated domains (LADs). LADs are marked by increased histone methylation levels and are physically or chemically tethered to NL via proteins such as lamina-associated polypeptide 2β (LAP2β). The spatial organization of LADs exerts stimulating effects on gene repression and cell function. Here, we propose a phase-field model of chromatin organization to address the mechanisms underlying the morphological regulation of LADs. The model includes chromatin-chromatin interactions, chromatin-lamina interactions, and epigenetic kinetics of acetylation and methylation. We find that the strength of chromatin-lamina interaction drives the peripheral localization of heterochromatin, and its competition with the chromatin-chromatin interactions plays a role in determining the LAD shape. We derive a relation for the LAD thickness in terms of the methylation rates and chromatin-lamina affinity, which we validate using whole-genome numerical simulations. Comparing simulations with super-resolution images of in-vitro nuclei under histone deacetylase (HDAC) inhibiting conditions quantitatively validates the model, presenting novel means of inferring physical parameters such as epigenetic rates and chromatin-lamina affinity from nuclei super-resolution images. Our findings suggest that the association of HDAC3 and LAP2β modulates the LAD organization, serving as a potential mechanism to respond to the microenvironmental stimuli. We numerically predict the whole-genome chromatin organization in nuclei under varying chemo-mechanical environments such as epigenetic inhibition and substrate stiffnesses. Our experimental results further validate our model while quantitatively estimating the histone methylation rate and chromatin-lamina affinity in each condition. Our work has significant relevance in understanding the roles of microenvironmental factors in regulating chromatin morphology, which provides insights into the cell response to vital biological processes, including development, cancer metastasis, and degenerative diseases.