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

本研究旨在深入研究一种新型lncRNA在表皮稳态紊乱中控制基因调控网络的特性。100多种人类遗传性皮肤病的特点是表皮内平衡缺陷，因此影响到五分之一以上的人口。虽然迄今为止已经确定了引起几种体内平衡皮肤疾病的突变，但对不平衡表皮体内平衡的表型后果的治疗仍然具有挑战性。长链非编码rna （lncRNAs）是许多细胞通路中基因表达的关键调控因子，包括皮肤分化的调控。我们的初步数据强烈表明，我们命名为lncP4的新型lncRNA在调节人类表皮的祖细胞区室中起着至关重要的作用，从而控制该组织的稳态平衡。我们建议在单细胞分辨率下，基于动态基因表达网络和染色质可及性的变化，分析正常和患病的人体器官型表皮中角质细胞群体的功能异质性。这将允许深入表征正常表皮和稳态皮肤病组织模型中稳态平衡的维持和丧失。此外，我们将确定lncRNA lncP4对这些过程的影响，包括其挽救体内平衡失衡的潜力。此外，本研究旨在分析lncP4在调节表皮祖细胞维持中的功能作用和作用方式。

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.