Noncircadian BMAL1-YAP activity amplifies persistent inflammation in aged epidermis.

Júlia Bonjoch, Paloma Solá, Sandra García-Mulero, Thomas Mortimer, Oscar Reina, Camille Stephan-Otto Attolini, Yekaterina A Miroshnikova, Sara A Wickström, Laura Álvarez, Salvador Aznar Benitah, Guiomar Solanas

Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. · pubmed

Paper

Abstract

Aging is characterized by persistent low-grade inflammation linked to impaired tissue homeostasis, yet the underlying molecular mechanisms remain poorly understood. The mammalian skin is a clinically relevant site of aging-driven inflammation associated with compromised barrier function, inefficient wound healing, elevated oxidative stress and DNA damage accumulation. Here we show that, in the murine epidermis, aging engages a previously uncharacterized BMAL1-YAP functional cooperation with enhanced binding at inflammation-related enhancers, amplifying target gene transcription. Independent of its circadian clock role, BMAL1 partners with the mechanosensitive cofactor YAP at enhancer regions to regulate epidermal identity genes. However, in aged skin, this cooperative binding undergoes a functional shift, enhancing the expression of inflammation-related genes, partially coregulated by NF-κB. In addition, aged pro-inflammatory IL-17 signaling activates YAP in a Hippo-independent manner. These findings unveil a transcriptional mechanism underlying epidermal aging, linking chromatin dynamics to inflammatory programs through rewiring of BMAL1-YAP-occupied enhancers, highlighting potential strategies to counteract chronic inflammation and restore tissue homeostasis during aging.

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Research summary

The paper identifies a specific molecular mechanism (BMAL1-YAP cooperation) that drives persistent inflammation in aged skin, linking circadian clock components to age-related tissue dysfunction. This represents an incremental advance in understanding the root causes of aging-related inflammation, specifically within the context of epidermal homeostasis.

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