Mechanical forces play critical roles in the function of living cells. However, the underlying mechanisms of how forces influence nuclear events remain elusive. Here, we show that chromatin deformation as well as force-induced transcription of a green fluorescent protein (GFP)-tagged bacterial-chromosome dihydrofolate reductase (DHFR) transgene can be visualized in a living cell by using three-dimensional magnetic twisting cytometry to apply local stresses on the cell surface via an Arg-Gly-Asp-coated magnetic bead. Chromatin stretching depended on loading direction. DHFR transcription upregulation was sensitive to load direction and proportional to the magnitude of chromatin stretching. Disrupting filamentous actin or inhibiting actomyosin contraction abrogated or attenuated force-induced DHFR transcription, whereas activating endogenous contraction upregulated force-induced DHFR transcription. Our findings suggest that local stresses applied to integrins propagate from the tensed actin cytoskeleton to the LINC complex and then through lamina–chromatin interactions to directly stretch chromatin and upregulate transcription.
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This work was supported by NIH R01 GM072744 (to N.W.) NIH R01 GM58460 (to A.S.B.), and funds from Huazhong University of Science and Technology, and Ministry of Science and Technology of China grant 2016YFA0101100. A.T. acknowledges partial support from Natural Sciences and Engineering Research Council (NSERC) of Canada through a PGS Doctoral Scholarship. R.S. acknowledges support from the NSF IGERT Program. N.W. acknowledges support from a Hoeft Professorship at University of Illinois at Urbana-Champaign.
The authors declare no competing financial interests.
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Tajik, A., Zhang, Y., Wei, F. et al. Transcription upregulation via force-induced direct stretching of chromatin. Nature Mater 15, 1287–1296 (2016). https://doi.org/10.1038/nmat4729
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