Matière et Systèmes Complexes (MSC), UMR 7057 CNRS, Université de Paris, Bâtiment Condorcet, Case 7056, 10 rue Alice Domon et Léonie Duquet, 75205, PARIS cedex 13, France.
Epigenetics and Cell Fate (EDC), UMR 7216 CNRS, Université de Paris, Bâtiment Lamarck, Case 7042, 35 rue Hélène Brion, 75205, PARIS cedex 13, France.
Sci Rep. 2020 Nov 26;10(1):20598. doi: 10.1038/s41598-020-75833-9.
Mechanical cues from the cellular microenvironment are converted into biochemical signals controlling diverse cell behaviours, including growth and differentiation. But it is still unclear how mechanotransduction ultimately affects nuclear readouts, genome function and transcriptional programs. Key signaling pathways and transcription factors can be activated, and can relocalize to the nucleus, upon mechanosensing. Here, we tested the hypothesis that epigenetic regulators, such as methyltransferase enzymes, might also contribute to mechanotransduction. We found that the SMYD3 lysine methyltransferase is spatially redistributed dependent on cell geometry (cell shape and aspect ratio) in murine myoblasts. Specifically, elongated rectangles were less permissive than square shapes to SMYD3 nuclear accumulation, via reduced nuclear import. Notably, SMYD3 has both nuclear and cytoplasmic substrates. The distribution of SMYD3 in response to cell geometry correlated with cytoplasmic and nuclear lysine tri-methylation (Kme3) levels, but not Kme2. Moreover, drugs targeting cytoskeletal acto-myosin induced nuclear accumulation of Smyd3. We also observed that square vs rectangular geometry impacted the nuclear-cytoplasmic relocalisation of several mechano-sensitive proteins, notably YAP/TAZ proteins and the SETDB1 methyltransferase. Thus, mechanical cues from cellular geometric shapes are transduced by a combination of transcription factors and epigenetic regulators shuttling between the cell nucleus and cytoplasm. A mechanosensitive epigenetic machinery could potentially affect differentiation programs and cellular memory.
细胞微环境中的力学线索被转化为控制多种细胞行为的生化信号，包括生长和分化。但目前尚不清楚机械转导如何最终影响核读数、基因组功能和转录程序。关键的信号通路和转录因子可以在机械感应时被激活，并重新定位到细胞核。在这里，我们测试了这样一个假设，即表观遗传调节剂，如甲基转移酶，也可能有助于机械转导。我们发现，在小鼠成肌细胞中，SMYD3 赖氨酸甲基转移酶的空间分布依赖于细胞的几何形状（细胞形状和纵横比）。具体来说，与正方形形状相比，细长的矩形形状通过减少核输入，使 SMYD3 更不容易进入细胞核。值得注意的是，SMYD3 既有核内底物，也有细胞质内底物。SMYD3 对细胞几何形状的分布与细胞质和核内赖氨酸三甲基化（Kme3）水平相关，但与 Kme2 无关。此外，针对细胞骨架肌动球蛋白的药物诱导了 Smyd3 的核内积累。我们还观察到，正方形与长方形的几何形状影响了几种机械敏感蛋白的核质重新定位，特别是 YAP/TAZ 蛋白和 SETDB1 甲基转移酶。因此，来自细胞几何形状的机械线索通过在细胞核和细胞质之间穿梭的转录因子和表观遗传调节剂的组合进行转导。机械敏感的表观遗传机制可能会影响分化程序和细胞记忆。
