HNRNPU and architectural lncRNAs as nuclear tethers of epithelial state stability.

Skin biology is commonly framed through signaling pathways that reprogram transcription in response to inflammatory and environmental cues. Here, a complementary perspective is proposed: epidermal homeostasis and disease recurrence may also depend on the physical organization of the genome within the nucleus. HNRNPU/SAF-A has emerged as an RNA-dependent architectural factor that links RNA binding to chromatin topology, while architectural long non-coding RNAs provide precedents for how RNA can scaffold nuclear compartments and influence higher-order genome organization. Building on these concepts, the Epidermal Differentiation Complex is considered as a tractable epidermal locus in which RNA-dependent nuclear tethering may help stabilize barrier gene programs. This framework further suggests that chronic inflammation could remodel chromatin architecture in ways that persist after apparent resolution, generating a "structural scar" that biases future responses. Although this model remains hypothetical, it is now experimentally testable. By integrating architectural RNA biology with epidermal differentiation and inflammatory memory, this Perspective provides a roadmap for investigating how nuclear structure may contribute to epithelial state stability and how it may be altered in inflammatory skin disease.