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Join Professor Ning Wang from University of Illinois Urbana-Champaign for a Force Talk entitled 'From integrins to CSK/LINC to LAP2β: long-range force transmission to stretch chromatin to upregulate transcription.'
Mechanical forces influence almost every aspect of cells and tissues but the mechanisms of force-induced gene expression remain poorly understood. We have discovered that chromatin is a mechanosensor and that chromatin is stretched milliseconds after application of a local cell surface stress via integrins, CSK, and LINC complexes. The extent of transgene DHFR (dihydrofolate reductase) rapid upregulation depends on the degree of chromatin stretching. Recently we have extended these findings on force-induced rapid upregulation of the transgene DHFR to endogenous genes egr-1 (early growth response-1) and Cav1 (caveolin-1), suggesting the force acts like a “super transcription factor”. We reveal that prestressed actin bundle anisotropy determines long-distance force propagation, the extent of chromatin stretching, and ensuing gene upregulation. We show that rapid gene upregulation depends on chromatin stretching but not compression. We have identified BAF and LAP2b as the proteins responsible for force transmission from nuclear lamina to chromatin to stretch chromatin domains and to activate genes via recruitments of RNA polymerase II to the promoter sites of demethylated H3K9me3. We have found that demethylated H3K9me3 leads to upregulation of self-renewal gene Sox2 in tumor repopulating cells. Together with our published evidence that cell softness and low CSK prestress play a central role in proliferation and metastasis of malignant tumor repopulating cells, we propose a mechanobiology model of tumor cell softness for tumor progression and dormancy that depends on relative stiffness of tumor cells and their extracellular matrices.
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At this event
Senior Lecturer in Experimental Biophysics
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