BMAL1 and YAP cooperate to hijack enhancers and promote inflammation in the aged epidermis [ChIP-Seq]

Ageing is characterised by persistent low-grade inflammation that is linked to impaired tissue homeostasis and functionality. However, the molecular mechanisms driving age-associated inflammation remain poorly understood. The mammalian skin is a clinically relevant site of ageing-driven inflammation associated with compromised barrier function, inefficient wound healing, elevated oxidative stress, and DNA damage accumulation. Here, we show that during ageing a previously uncharacterised BMAL1–YAP transcriptional complex displays enhanced binding at inflammation-related enhancers, amplifying the transcription of their target genes. Independent of its known role as a core circadian clock component, we report that BMAL1 partners with the mechanosensitive transcriptional cofactor YAP at enhancer regions to regulate epidermal identity genes. However, in aged skin, this BMAL1–YAP cooperative binding undergoes a functional shift, enhancing the activity of enhancers of inflammation-related genes, co-regulated by NF-κB. Interestingly, aged pro-inflammatory signals from the IL-17 pathway activate YAP in a Hippo-independent manner. These findings unveil a transcriptional mechanism underlying epidermal ageing, linking chromatin dynamics to inflammatory transcriptional programs through BMAL1–YAP-bound enhancer rewiring. By elucidating how ageing reprograms transcriptional networks, our work highlights potential strategies to counteract chronic inflammation and restore tissue homeostasis across age-related loss of functionality.