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

该提案旨在深入了解一种新的lncRNA在控制表皮稳态紊乱的基因调控网络中的特征。超过100种人类遗传性皮肤病的特征在于表皮稳态缺陷，从而影响超过五分之一的人口。虽然迄今为止已经鉴定了引起几种稳态皮肤疾病的突变，但治疗不平衡的表皮稳态的表型后果仍然具有挑战性。长链非编码RNA（lncRNA）是许多细胞途径中基因表达的关键调节因子，包括皮肤分化的调节。我们的初步数据有力地表明了一种我们命名为lncP 4的新型lncRNA在调节人表皮祖细胞区室中的关键作用-从而控制该组织的稳态平衡。我们建议分析功能异质性的角质形成细胞群体在正常和患病的人类器官型人类表皮的基础上动态基因表达网络和染色质可及性的变化，在所有阶层的单细胞分辨率。这将允许在正常表皮和稳态皮肤病的组织模型中深入表征稳态平衡的维持和丧失。此外，我们将确定lncRNA lncP 4对这些过程中的每一个的影响，包括其拯救稳态失衡的潜力。此外，该建议旨在分析lncP 4在调节表皮祖细胞维持中的功能作用和作用模式。

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.