Department of Mechanical Science and Engineering, The Grainger College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
Sci Adv. 2020 Apr 1;6(14):eaay9095. doi: 10.1126/sciadv.aay9095. eCollection 2020 Apr.
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 or endogenous genes and 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 and at the nuclear interior and activates mechano-nonresponsive gene 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、生理和疾病中发挥着重要作用，但力如何转化为基因转录仍然难以捉摸。在这里，我们表明，通过整合素施加的低频循环力而非 100 Hz 力可快速上调转基因或内源性基因和的转录。基因上调与力频率不遵循弱幂律。核内的力诱导转录上调与组蛋白 H3 赖氨酸-9 三甲基化 (H3K9me3) 的去甲基化有关，而核外周没有转录上调与抑制 Pol II 募集到启动子位点的 H3K9me3 有关。H3K9me3 去甲基化诱导 Pol II 募集，并增加核内力诱导的和的转录，激活核外周机械非反应性基因，而 H3K9me3 高甲基化则有相反的效果。我们的发现表明，内源性机械反应基因的快速上调依赖于 H3K9me3 的去甲基化。
