Dissecting the impact of lncRNA-controlled gene regulatory networks in defects of epidermal homeostasis

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This proposal seeks insight into in depth characterization of a novel lncRNA in controlling gene regulatory networks in disorders of epidermal homeostasis. More than 100 human genetic skin diseases are characterized by defective epidermal homeostasis, thus affecting over one fifth of the population. While mutations causing several homeostatic skin disorders have been identified to date, treatment of the phenotypic consequences of imbalanced epidermal homeostasis remains challenging. Long non-coding RNAs (lncRNAs) are key regulators of gene expression in many cellular pathways, including regulation of skin differentiation. Our preliminary data strongly indicates a crucial role of a novel lncRNA we named lncP4, in regulating the progenitor cell compartment of human epidermis – thus controlling the homeostatic balance of this tissue. We propose to analyze functional heterogeneity of keratinocyte populations in normal and diseased human organotypic human epidermis based on dynamic gene expression networks and changes in chromatin accessibility across all strata in single cell resolution. This will allow for in depth characterization of maintenance and loss of homeostatic balance in normal epidermis and in a tissue model for homeostatic skin disease. In addition, we will identify the impact of lncRNA lncP4 on each of these processes, including its potential for rescue of homeostatic imbalances. Furthermore, this proposal is aimed at analyzing lncP4 functional roles and modes of action in regulating epidermal progenitor cell maintenance.