Cell geometry dictates TNF?-induced genome response.

ABSTRACT: 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 TNF? signaling. We stabilized NIH 3T3 fibroblasts into rectangular anisotropic or circular isotropic geometries and stimulated them with TNF? and analyzed nuclear translocation of transcription regulators -NF?B (p65) and MKL and downstream gene-expression patterns. We found that TNF? induces geometry-dependent actin depolymerization, which enhances I?B 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-TNF? interplay reveals a geometry-dependent gene-expression pattern. At a functional level, we find cell geometry affects TNF?-induced cell proliferation. Our results provide compelling evidence that fibroblasts, depending on their geometries, elicit distinct cellular responses for the same cytokine.

SUBMITTER: Mitra A 

PROVIDER: S-EPMC5441774 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature