Mechanical forces play important roles in development, physiology, and diseases, but how force is transduced into gene transcription remains elusive. Here, we show that transcription of transgene DHFR or endogenous genes egr-1 and Cav1 is rapidly up-regulated in response to cyclic forces applied via integrins at low frequencies but not at 100 Hz. Gene up-regulation does not follow the weak power law with force frequency. Force-induced transcription up-regulation at the nuclear interior is associated with demethylation of histone H3 lysine-9 trimethylation (H3K9me3), whereas no transcription up-regulation near the nuclear periphery is associated with H3K9me3 that inhibits Pol II recruitment to the promoter site. H3K9me3 demethylation induces Pol II recruitment and increases force-induced transcription of egr-1 and Cav1 at the nuclear interior and activates mechano-nonresponsive gene FKBP5 near the nuclear periphery, whereas H3K9me3 hypermethylation has opposite effects. Our findings demonstrate that rapid up-regulation of endogenous mechanoresponsive genes depends on H3K9me3 demethylation.

机械力在发育，生理学和疾病中起着重要作用，但是如何将力传递到基因转录中仍然难以捉摸。在这里，我们表明转基因DHFR或内源基因egr-1和Cav1的转录响应于整联蛋白在低频而不是在100 Hz时施加的循环力，它会迅速上调。基因上调不遵循具有强制频率的弱幂定律。力诱导的在核内部的转录上调与组蛋白H3赖氨酸9三甲基化（H3K9me3）的去甲基化相关，而在核周边附近没有转录上调与抑制Pol II募集到启动子位点的H3K9me3相关。H3K9me3去甲基化诱导Pol II募集并增加核内的egr-1和Cav1的力诱导转录并激活机械无应答基因FKBP5H3K9me3高甲基化具有相反的作用。我们的研究结果表明内源性机械反应基因的快速上调取决于H3K9me3脱甲基。