MeCP2-driven chromatin organization controls nuclear stiffness.

Cellular differentiation is driven by epigenetic modifiers and readers, including the methyl CpG binding protein 2 (MeCP2), whose level and mutations cause the neurological disorder Rett syndrome. During differentiation, most of the genome gets densely packed into heterochromatin, whose function has been simplistically viewed as gene silencing. However, gene expression changes reported in mutations leading to Rett syndrome have failed to be a predictor of disease severity. Here we show that MeCP2 increases nuclear stiffness in a concentration-dependent manner and dependent on its ability to cluster heterochromatin during differentiation. MeCP2-dependent stiffness increase could not be explained by changes in the expression of mechanobiology-related genes, but we found that it is disrupted by Rett syndrome mutations and correlated with disease severity. Our results highlight the impact of chromatin organization on the mechanical properties of the cell as an alternative or complementary mechanism to changes in cytoskeleton components.