(B-60) Mesoscale morphological regulation of lamina-associated domains in response to substrate stiffness

Introduction:: In interphase nuclei, chromatin reorganization in response to chemo-mechanical stimuli leads to the repression and activation of chromatin domains, a significant portion of which are associated with the nuclear lamina (NL) called lamina-associated domains (LADs). The mechanisms driving the organization of LADs which are generally transcriptionally inactive in response to external cues remains unclear.

Materials and Methods:: In this study, a phase-field model was developed to understand how the mesoscale (~100 nm) morphological regulation of LADs occurs where conventional modeling approaches cannot be applied to this scale. Our model was developed to incorporate chromatin-chromatin interactions, chromatin-lamina affinities, and epigenetic reactions that cause methylation and acetylation of the histone. The investigation focuses on the interplay between chromatin-lamina affinities and epigenetic reactions, specifically how substrate stiffness affects the size and shape of LADs. A mathematical model considering the finite size effects of chromatin was also incorporated to study the mutual effects between the formation of LADs and inner nucleus heterochromatin domains. Additionally, a novel image based determination framework of biophysical parameters enhanced by stochastic optical reconstruction microscopy (STORM) images was applied to validate our model predictions.


Results, Conclusions, and Discussions:: We find that the strength of chromatin-lamina affinities drives the peripheral localization of heterochromatin, and the competition of these interactions with the epigenetic reactions determines a morphological transition between fully spread-out LADs and smaller discrete LADs. We develop an analytical model that relates LAD thickness to methylation rates and chromatin-lamina affinities, and we validate this model using genome-wide numerical simulations. Additionally, we investigate the in-vitro effect of microenvironmental stiffness on LAD morphology and suggest that changes in stiffness modulate both epigenetic reactions and chromatin-lamina affinities by regulating the cross-nuclear shuttling of enzymes like HDAC, which in turn affects gene expression.


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