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Mechanobiology of Disease
Poster Abstracts
116
51-POS
Board 51
Cell-Geometric-Constraints Differentially Regulate Tnfα-Mediated Gene Expression
Programs
Aninda Mitra
1,2
, Saradha Venkatachalapathy
1
, Prasuna Ratna
1
, Yejun Wang
1
, G V
Shivashankar
1,2
.
1
Mechanobiology Institute, National University of Singapore, Singapore, Singapore,
2
FIRC
Institute of Molecular Oncology (IFOM), Milan, Italy.
Cells in physiology integrate local soluble and mechanical signals to regulate gene expression
programs. While the individual roles of these signals on nuclear mechanotransduction are well
studied, the cellular responses to the combined chemical and physical signals are less explored.
Here, we investigate the crosstalk between cellular geometric-constraints and its integration to
TNFα signaling. We stabilize NIH3T3 fibroblasts in polarized or isotropic states and stimulate
them with TNFα to analyze NFκB(p65) nuclear localization and its downstream target gene-
expression. We find that cell mechanics influences TNFα-induced actin-depolymerization which
enhances IκB degradation and p65 nuclear translocation and sequestration of RNA-polymerase-
II foci with p65. This also affects nuclear exit of transcription co-factor MKL in polarized cells.
Further, global transcription profile of cells under matrix-TNFα interplay, reveal a geometry-
dependent genetic response. Our results provide compelling evidence that cells, depending on
their mechanical states, elicit distinct cellular responses for the same cytokine.