The palmoplantar epidermis, in adapting to the exceptional mechanical strain it bears during locomotion, is histologically and molecularly distinct from other skin body sites. The mechanisms specifying and maintaining its unique identity remain incompletely defined. Here we identify the type I keratin 9 (KRT9/K9), a protein uniquely expressed in palmoplantar epidermis, as a key modulator of mechanosensitive YAP1 signalling in response to postnatal mechanical compression. K9 loss-of-function variants driving KRT9-pEDD, a palmoplantar epidermal differentiation disorder, result in aberrant YAP1 subcellular partitioning and elevated levels of the stress-induced keratin 16 (KRT16/K16). Krt9 null mice recapitulate these molecular phenotypes as early as postnatal day 3. We further identify dynamic, YAP1-dependent regulation of Krt16/K16, upstream of and necessary for Krt9/K9 expression, during early postnatal development in situ and in response to mechanical compression of keratinocytes ex vivo, highlighting the role of mechanical stress in epidermal specification. Mechanistically, K9 interacts with the YAP1 binding protein 14-3-3σ and sequesters YAP1 in the cytoplasm, inhibiting its transcriptional activity; these functions are disrupted by KRT9-pEDD-causing variants in K9. Finally, we show that genetic or pharmacological inhibition of YAP1 ameliorates palmoplantar keratoderma in Krt9 null mice. These findings reveal a role for mechanical cues in specification and maintenance of palmoplantar skin and suggest new therapeutic interventions for inherited palmoplantar epidermal differentiation disorders. Steiner et al. propose that keratin 9 (K9) interacts with 14-3-3, sequestering YAP1 in the cytoplasm and inhibiting YAP1 activity. They identify dysregulated YAP in palmoplantar keratinization diseases, with K9 as a downstream regulator of YAP.
Ferroptosis is an iron-dependent type of cell death caused by excessive membrane lipid peroxidation. It remains a challenge to detect ferroptotic cells, especially in in vivo settings, hindering translational studies. Here we discover that a reducing reagent-resistant (3R) dimer of the transferrin receptor 1 (TfR1) is a highly specific indicator for lipid peroxidation. The 3R dimer is elevated in cells when ferroptosis is induced, either by pharmacological agents or by genetic perturbations. Furthermore, the 3R dimer can be used to detect disease-associated ferroptosis in tissue and in extracellular vesicles isolated from mouse or patient plasma. Given the near-ubiquitous expression of TfR1, we posit that the 3R dimer may function as a ferroptosis marker with widespread potential utility for basic and translational studies. He et al. report the upregulation of a reducing reagent-resistant form of the transferrin receptor 1 dimer during lipid peroxidation and demonstrate its utility in detecting ferroptosis in tissue lysates and extracellular vesicles from mice and humans.
Organogenesis marks one of the most dynamic periods of early human embryonic development. Although the morphological features of this period have been described, the underlying transcriptional and metabolic landscapes remain poorly understood owing to the lack of an integrated spatial strategy. We present spatial transcriptomic and metabolomic maps of a Carnegie stage 12 (CS12) human embryo, co-registered with embryonic anatomy to generate a unified spatial multi-omic framework. Unsupervised clustering of the spatial transcriptomic data identified 17 cell populations covering the major organ primordia. Notably, we observed spatially separable hepatocyte- and cholangiocyte-lineage primed transcriptional programmes within the liver primordium, and detected cardiac outflow tract and sinoatrial node progenitors at CS12. Furthermore, integration of gene and metabolite abundance highlighted regional associations between transcription factors and metabolic pathways underpinning lineage specification. Our work presents a spatially resolved multi-omic atlas of a human embryo at the onset of organogenesis. Wang et al. map a Carnegie stage 12 human embryo with spatial transcriptomics and metabolomics.
RNAs can associate with the surface of diverse cell types, yet the functions of specific RNA species on primary immune cells remain unclear. Here, utilizing methods developed to profile, image and quantify surface RNAs in rare primary cell populations, we found that Y RNAs, a family of small noncoding RNAs, preferentially localize to human monocyte surface. In an exploratory pooled inflammatory bowel disease cohort, the proportion of cell-surface-Y-RNA-positive peripheral monocytes was markedly higher in patients with inflammatory bowel disease than in healthy donors or individuals with irritable bowel syndrome. In vivo depletion of cell-surface Y RNAs ameliorates disease activity in mice with colitis. Mechanistically, cell-surface Y RNAs co-cluster with Toll-like receptors TLR2 and TLR4, bind extracellular histones and promote receptor-mediated histone recognition, thereby activating NF-κB and AP-1 signalling and increasing IL6 expression and IL-6 secretion. These findings identify cell-surface Y RNAs as previously unrecognized amplifiers of inflammatory activation. Jiang, He, Xu, Zheng et al. report a functional role for cell-surface Y RNAs in modulating extracellular histone-induced inflammatory signalling and cytokine secretion, which may contribute to the pathogenesis of inflammatory bowel disease.
