H3K27me3 Drives Constricted Migration Induced 3D Genome Rewiring in Melanoma
Repeated exposure of neoplastic cells to mechanical stresses during metastasis can drive stable morphological and physiological changes. We previously showed that A375 human melanoma cells subjected to 10 rounds of constricted migration ("Bottom-10 cells") became significantly more migratory and exhibited H3K9me3 relocalization, transcriptional remodeling, and chromatin compartment changes…
Human melanoma cells subjected to limited mobility displayed considerable morphological and physiological alterations. Previous research revealed that A375 human melanoma cells exposed to ten instances of restricted movement (Bottom-10 cells) exhibited heightened migratory capacity and distinct epigenetic alterations compared to their parent cells.
The persistent nature of these traits across successive cell divisions led investigators to suspect the involvement of specific epigenetic mechanisms. In this study, researchers aimed to identify these epigenetic factors and their roles in orchestrating constricted migration-induced 3D genome rewiring in melanoma.
By employing CUT&RUN analysis and computational modeling, the team identified key histone modifications that predict locus stability in the B and A compartments for parental cells. These modifications were H3K9me3 for B compartment stability and H3K4me1 for A compartment stability. Upon exposure to constricted migration, the team observed a dynamic shift in H3K27me3 levels, which predicted changes in the A-to-B compartment.
The researchers further demonstrated that alterations in H3K27me3 enrichment correlated with shifts in gene regulation and chromatin compartment changes between Bottom-10 and parental cell populations.
To investigate the potential of H3K27me3 inhibition in modulating migratory potential and phenotype memory, the researchers treated the Bottom-10 cells with an inhibitor targeting EZH1/2, a component of the EZH2 protein complex responsible for H3K27me3 methylation. The results showed that inhibiting H3K27me3 deposition generally reduced migration efficiency, with a more pronounced effect on constricted than unconstricted migration.
This reduction was linked to decreased H3K27me3 enrichment and the reversal of certain compartment changes in Bottom-10 cells. However, acute treatment did not result in a permanent reversal of the highly migratory Bottom-10 phenotype, as cells reverted to their initial state upon drug removal.
Interestingly, chronic inhibition of H3K27me3 across multiple rounds of constricted migration led to a significant reduction in the proportion of cells capable of migrating. Remarkably, some cells managed to migrate despite chronic inhibition, acquiring typical Bottom-10 H3K27me3 and compartment changes despite the treatment. These findings underscore H3K27me3 as a crucial player in establishing and maintaining constricted migration-induced 3D genome changes in melanoma cells.
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