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Transcription upregulation via force-induced direct stretching of chromatin

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Abstract

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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Figure 1: Strategy of visualizing chromatin under force.
Figure 2: The extent of chromatin stretching depends on stress directions.
Figure 3: Transcription increases with the extent of chromatin stretching.
Figure 4: Rapid initiation of force-induced gene transcription.
Figure 5: Structural basis of force transfer to stretch chromatin.
Figure 6: A model for direct force impact on gene activation.

Change history

  • 27 September 2016

    In the version of this Article originally published the image in Fig. 1e was incorrect. This has been corrected in all versions of the Article.

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Acknowledgements

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.

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N.W. and A.S.B. conceived the project. N.W., A.S.B., A.T., Y.Z., F.W. and J.S. designed the project. A.T., Y.Z., F.W., J.S., Q.J., W.Z., R.S. and N.K. performed experiments and analyses. N.W., A.T., F.W., J.S. and A.S.B. wrote the manuscript with inputs from all other authors.

Corresponding authors

Correspondence to Andrew S. Belmont or Ning Wang.

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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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