The ability of cells to sense and respond to mechanical signals is essential for many biological processes that form the basis of cell identity, tissue development and maintenance. This process, known as mechanotransduction, involves crucial feedback between mechanical force and biochemical signals, including epigenomic modifications that establish transcriptional programs. These programs, in turn, reinforce the mechanical properties of the cell and its ability to withstand mechanical perturbation. The nucleus has long been hypothesized to play a key role in mechanotransduction due to its direct exposure to forces transmitted through the cytoskeleton, its role in receiving cytoplasmic signals and its central function in gene regulation. However, parsing out the specific contributions of the nucleus from those of the cell surface and cytoplasm in mechanotransduction remains a substantial challenge. In this Review, we examine the latest evidence on how the nucleus regulates mechanotransduction, both via the nuclear envelope (NE) and through epigenetic and transcriptional machinery elements within the nuclear interior. We also explore the role of nuclear mechanotransduction in establishing a mechanical memory, characterized by a mechanical, epigenetic and transcriptomic cell state that persists after mechanical stimuli cease. Finally, we discuss current challenges in the field of nuclear mechanotransduction and present technological advances that are poised to overcome them.

Funding

Our work in this area was supported by awards from the National Institutes of Health (R01 HL082792, R01 1AR084664, and R35 GM153257 to J.L.), the National Science Foundation (URoL-2022048 to J.L.), the Volkswagen Foundation (A130142 to J.L.), the Leducq Foundation (20CVD01 and 24CVD03 to J.L.), the American Heart Association (Postdoctoral Fellowship 23POST1023021 to J.L.) and a Center for Vertebrate Genomics Scholar Award from Cornell University to J.L. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Deposited in PMC for release after 12 months.

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