دورية أكاديمية
PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis
| العنوان: | PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis |
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| المؤلفون: | Jokl, Elliot, Mullan, Aoibheann F, Simpson, Kara, Birchall, Lindsay, Pearmain, Laurence, Martin, Katherine, Pritchett, James, Raza, Sayyid, Shah, Rajesh, Hodson, Nigel W, Williams, Craig J, Camacho, Elizabeth, Zeef, Leo, Donaldson, Ian, Athwal, Varinder S, Hanley, Neil A, Piper Hanley, Karen |
| المصدر: | Jokl , E , Mullan , A F , Simpson , K , Birchall , L , Pearmain , L , Martin , K , Pritchett , J , Raza , S , Shah , R , Hodson , N W , Williams , C J , Camacho , E , Zeef , L , Donaldson , I , Athwal , V S , Hanley , N A & Piper Hanley , K 2023 , ' PAK1-dependent mechanotransduction enables myofibroblast nuclear adaptation and chromatin organization during fibrosis ' , Cell Reports , vol. 42 , no. 11 , 113414 .... |
| سنة النشر: | 2023 |
| المجموعة: | The University of Manchester: Research Explorer - Publications |
| مصطلحات موضوعية: | Humans, Myofibroblasts/pathology, Pulmonary Fibrosis/pathology, Cell Differentiation, Mechanotransduction, Cellular, Cicatrix/pathology, Fibrosis, Chromatin/metabolism, p21-Activated Kinases/metabolism |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://research.manchester.ac.uk/en/publications/a24d5c48-f33f-4099-87b6-8e7832d2013aTest |
| DOI: | 10.1016/j.celrep.2023.113414 |
| الإتاحة: | https://doi.org/10.1016/j.celrep.2023.113414Test https://research.manchester.ac.uk/en/publications/a24d5c48-f33f-4099-87b6-8e7832d2013aTest http://www.scopus.com/inward/record.url?scp=85176921518&partnerID=8YFLogxKTest https://www.mendeley.com/catalogue/559916c3-d100-387d-9ef4-22196d1d8169Test/ |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.FD0AADF9 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.celrep.2023.113414 |
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