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ABSTRACT Extracellular matrix stiffness is enhanced in cancer and fibrosis; however, there is limited knowledge on how matrix mechanics modulate expression and signaling of the methyltransferase G9a. Here, we show that matrix stiffness and transforming growth factor (TGF)‐β1 signaling together regulate G9a expression and the levels of the histone mark H3K9me2. Suppressing the activity and expression of G9a attenuates TGFβ1‐induced alpha smooth muscle actin (αSMA) and N‐cadherin expression and cell morphology changes in mammary epithelial cells cultured on stiff substrata. Knockdown of G9a increases the expression of large tumor suppressor kinase 2 (LATS2) and decreases the nuclear localization of yes associated protein (YAP). Furthermore, inhibition of LATS promotes an increase in YAP nuclear localization and αSMA expression, while inhibition of YAP attenuates αSMA expression. Overall, our findings indicate that a G9a‐LATS‐YAP signaling cascade regulates mammary epithelial cell response to matrix stiffness and TGFβ1.
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YAP-mediated mechanotransduction tunes the macrophage inflammatory response
Macrophages are innate immune cells that adhere to the extracellular matrix within tissues. However, how matrix properties regulate their function remains poorly understood. Here, we report that the adhesive microenvironment tunes the macrophage inflammatory response through the transcriptional coactivator YAP. We find that adhesion to soft hydrogels reduces inflammation when compared to adhesion on stiff materials and is associated with reduced YAP expression and nuclear localization. Substrate stiffness and cytoskeletal polymerization, but not adhesive confinement nor contractility, regulate YAP localization. Furthermore, depletion of YAP inhibits macrophage inflammation, whereas overexpression of active YAP increases inflammation. Last, we show in vivo that soft materials reduce expression of inflammatory markers and YAP in surrounding macrophages when compared to stiff materials. Together, our studies identify YAP as a key molecule for controlling inflammation and sensing stiffness in macrophages and may have broad implications in the regulation of macrophages in health and disease.
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- Award ID(s):
- 1763272
- PAR ID:
- 10222848
- Date Published:
- Journal Name:
- Science Advances
- Volume:
- 6
- Issue:
- 49
- ISSN:
- 2375-2548
- Page Range / eLocation ID:
- eabb8471
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1126/sciadv.abb8471
