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Mol Biol Cell. 2018 Sep 26:mbcE18040256. doi: 10.1091/mbc.E18-04-0256. [Epub ahead of print]

Compressive force induces reversible chromatin condensation and cell geometry dependent transcriptional response.

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Mechanobiology Institute and Department of Biological Sciences, National University of Singapore 117411, Singapore.
Center for Engineering Mechanobiology, University of Pennsylvania, PA, USA.
FIRC Institute for Molecular Oncology (IFOM), Milan 20139, Italy.


Fibroblasts exhibit heterogeneous cell geometries in tissues and integrate both mechanical and biochemical signals in their local microenvironment to regulate genomic programs via chromatin remodelling. While in connective tissues fibroblasts experience tensile and compressive forces (CFs), the role of compressive forces in regulating cell behaviour and in particular, the impact of cell geometry in modulating transcriptional response to such extrinsic mechanical forces is unclear. Here, we show that CF on geometrically well-defined mouse fibroblast cells reduces actomyosin contractility and shuttles Histone Deacetylase 3 (HDAC3), into the nucleus. HDAC3 then triggers an increase in the heterochromatin content by initiating removal of acetylation marks on the histone tails. This suggests that, in response to CF, fibroblasts condense their chromatin and enter into a transcriptionally less active and quiescent states as also revealed by transcriptome analysis. Upon removal of CF, the alteration in chromatin condensation was reversed. We also present a quantitative model linking CF dependent changes in actomyosin contractility leading to chromatin condensation. Further, transcriptome analysis also revealed that the transcriptional response of cells to CF was geometry dependent. Collectively, our results suggest that CFs induce chromatin condensation and geometry dependent differential transcriptional response in fibroblasts that allows maintenance of tissue homeostasis. [Media: see text] [Media: see text] [Media: see text].


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