Histone acetylation alters the nuclear morphology and architecture of human mesenchymal stem cells in a rigidity-dependent manner.

Nuclear morphology, which is closely linked to various cell functions and disease states, is known to be modulated by mechanical stimuli and chromatin modifications. In many pathological contexts such as cancer, fibrosis, and aging, changes in tissue stiffness coincide with extensive epigenetic remodeling, yet these two regulatory mechanisms have always been studied in isolation. Since cells in vivo are simultaneously subjected to both mechanical and chromatin driven perturbations, it is important to understand how these two signals work together to shape nuclear mechanics and architecture. In this study, we investigated the interplay between substrate rigidity and histone acetylation, mediated by the histone deacetylase inhibitor (HDACi) valproic acid (VA), in modulating nuclear morphology in human mesenchymal stem cells (hMSCs) cultured on substrates of varying rigidities. We found that VA-induced chromatin decondensation diminished the effects of soft substrates on nuclear morphological parameters, a change not observed on stiff substrates. Furthermore, we showed that the reduction in nuclear stiffness with VA treatment on both substrates was independent of lamin expression, highlighting chromatin decondensation as a key determinant of the observed change in nuclear stiffness. Moreover, we observed that nuclear wrinkling was pronounced in cells cultured on soft substrates but was markedly reduced following VA treatment, whereas cells on stiff substrates exhibited only minimal wrinkling that remained unaltered in the presence of VA. Together, our findings suggest that chromatin remodeling via HDACi can override substrate-dependent nuclear mechanotransduction on soft substrates. This study underscores the importance of mechano-epigenetic interactions and offers new insights into the epigenetic regulation of nuclear mechanics with potential implications for pathologies associated with nuclear morphology.