Jokl, Elliot, Mullan, Aoibheann F, Simpson, Kara, Birchall, Lindsay, Pearmain, Laurence, Martin, Katherine, Pritchett, James, Raza, Sayyid, Shah, Rajesh, Hodson, Nigel W et al (show 7 more authors)
(2023)
PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis.
Cell reports, 42 (11).
p. 113414.
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Abstract
Myofibroblasts are responsible for scarring during fibrosis. The scar propagates mechanical signals inducing a radical transformation in myofibroblast cell state and increasing profibrotic phenotype. Here, we show mechanical stress from progressive scarring induces nuclear softening and de-repression of heterochromatin. The parallel loss of H3K9Me3 enables a permissive state for distinct chromatin accessibility and profibrotic gene regulation. Integrating chromatin accessibility profiles with RNA expression provides insight into the transcription network underlying the switch in profibrotic myofibroblast states, emphasizing mechanoadaptive regulation of PAK1 as key drivers. Through genetic manipulation in liver and lung fibrosis, loss of PAK1-dependent signaling impairs the mechanoadaptive response in vitro and dramatically improves fibrosis in vivo. Moreover, we provide human validation for mechanisms underpinning PAK1-mediated mechanotransduction in liver and lung fibrosis. Collectively, these observations provide insight into the nuclear mechanics driving the profibrotic chromatin landscape in fibrosis, highlighting actomyosin-dependent mechanisms as potential therapeutic targets in fibrosis.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Cicatrix, Chromatin, Humans, Pulmonary Fibrosis, Fibrosis, Mechanotransduction, Cellular, Cell Differentiation, p21-Activated Kinases, Myofibroblasts |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Population Health |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 17 Jan 2024 11:13 |
| Last Modified: | 17 Jan 2024 11:14 |
| DOI: | 10.1016/j.celrep.2023.113414 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3177880 |
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