Epigenetic Reactions and Chromatin-lamina Interactions Synergistically Regulate the Morphology of Lamina-associated Domains

Lamina-associated domains (LADs) constitute a significant portion of transcriptionally silent chromatin in eucaryotic nuclei. The spatial organization of LADs exerts stimulating effects on gene repression and cell function. To elucidate the mechanisms underlying the morphological modulation of LADs, we propose a theoretical model incorporating chromatin-chromatin interactions, chromatin-lamina interactions, and epigenetic regulations. Our model predicts a phase-diagram of LAD thickness, which is determined by the synergistic contributions of both the strength of chromatin-lamina interactions and the level of histone methylation. The model is validated for in-vitro nuclei under the alternation of chemo-mechanical cues such as epigenetic suppression and substrate stiffening. Our model serves as a novel tool to use super-resolution images to quantitatively infer the histone methylation rate as well as the strength of chromatin-lamina interactions under different chemo-mechanical stimuli. Our findings suggest that histone deacetylase (HDAC) together with chromatin anchoring lamina-associated polypeptide 2β (LAP2β) modulates the LAD organization, serving as a potential mechanism driving the response to the microenvironmental stimuli. Our work has significant relevance in understanding the roles of microenvironmental factors in regulating chromatin morphology, providing insights into the cell response to vital biological processes, including development, cancer metastasis, and degenerative diseases.