Lamour, G. | bioRxiv Science

bioRxiv2025

Epigenetic control of nuclear mechanics and cellular migration via histone H3 lysine 9 methylation at Lamina-Associated Domains

Chromatin not only stores genetic information but also regulates nuclear mechanical properties. However, how epigenetic modifications, such as histone H3 lysine 9 trimethylation (H3K9me3), shape chromatin states at lamina-associated domains (LADs) and influence nuclear mechanics remains unclear. Here, we reveal an unexpected and paradoxical role of the pro-oncogenic H3K9 lysine methyltransferase (KMT) SETDB1, frequently overexpressed in many cancers, in LAD regulation. Rather than reinforcing heterochromatin, SETDB1 overexpression prevents SUV39H1-driven H3K9me3 accumulation at LADs, thereby disrupting the peripheral heterochromatin. Reducing SETDB1 levels, or disrupting its interaction with SUV39H1, enables SUV39H1 to restore LAD-localized H3K9me3 and re-establish an epithelial-like heterochromatin architecture. Heterochromatin reorganization upon SETDB1 reduction stiffens the nucleus and increases cell viscosity, thereby reducing cancer cell deformability and migratory capacity. Strikingly, these mechanical effects occur without major transcriptional changes, demonstrating that chromatin architecture itself critically shapes nuclear mechanics and cell motility. Our findings reveal a previously unrecognized role of the SETDB1-SUV39H1 axis in nuclear biomechanics, highlighting it as a potential determinant of cancer cell migration and metastatic processes.

molecular biology↗

bioRxiv2025

Atomic Force Microscopy reveals differences in mechanical properties linked to cortical structure in mouse and human oocytes

Cell mechanical properties regulate biological processes such as oocyte development. Cortical tension is regulated via actomyosin cortex remodeling to ensure optimal oocyte quality. However, the evolution of other mechanical parameters and their relationship with cortex structure remain poorly understood in mammalian oocytes. In this work, we propose a methodology combining multiple mechanical parameters measured through Atomic Force Microscopy to investigate the relationship between oocyte mechanical properties and cortex organization. By studying mouse oocytes at various stages of development, along with engineered ones with specific cortex organization, we demonstrate that a thin actin cortex corresponds to stiff oocytes while a thick one is associated with softer oocytes. We further reveal that maternal age, a critical factor for fertility, affects mouse oocytes mechanics correlating with alterations in their cortex structure. Finally, we show that the evolution of mechanical properties differs between human and mouse oocyte development, highlighting species-specific differences in cortex organization.

biophysics↗