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Cell geometry dictates TNFα-induced genome response

Significance Cells experience distinct forces within the tissue microenvironment, and their geometry-dependent differential responses to various cytokines are important in the maintenance of their cellular homeostasis. Using micropatterned substrates to alter cell geometry, we show that TNFα stimulation results in differential nuclear localization of the downstream transcription factors and modular changes in gene-expression patterns. Our results highlight the importance of the intrinsic geometric properties of a cell in determining its response to a biochemical signal. Alterations to this cellular homeostasis may result in physiological abnormalities at single-cell level, leading to diseases like fibrosis and cancer. Cells in physiology integrate local soluble and mechanical signals to regulate genomic programs. Whereas the individual roles of these signals are well studied, the cellular responses to the combined chemical and physical signals are less explored. Here, we investigated the cross-talk between cellular geometry and TNFα signaling. We stabilized NIH 3T3 fibroblasts into rectangular anisotropic or circular isotropic geometries and stimulated them with TNFα and analyzed nuclear translocation of transcription regulators –NFκB (p65) and MKL and downstream gene-expression patterns. We found that TNFα induces geometry-dependent actin depolymerization, which enhances IκB degradation, p65 nuclear translocation, nuclear exit of MKL, and sequestration of p65 at the RNA-polymerase-II foci. Further, global transcription profile of cells under matrix-TNFα interplay reveals a geometry-dependent gene-expression pattern. At a functional level, we find cell geometry affects TNFα-induced cell proliferation. Our results provide compelling evidence that fibroblasts, depending on their geometries, elicit distinct cellular responses for the same cytokine.