The uc.291 transcript controls keratinocytes differentiation by physical interaction with ACTL6A and subsequent induction of transcription of the genes belonging to the epidermal differentiation complex (EDC). Uc.291 is also implicated in the dedifferentiation phenotype seen in poorly differentiated cutaneous squamous cell carcinomas. Here, we would like to investigate the contribution of uc.291 to the unbalanced differentiation state of keratinocytes observed in hyperproliferative skin disorders, e. g., psoriasis. Psoriasis is a multifactorial inflammatory disease, caused by alteration of keratinocytes homeostasis. The imbalanced differentiation state, triggered by the infiltration of immune cells, represents one of the events responsible for this pathology. In the present work, we explore the role of uc.291 and its interactor ACTL6A in psoriasis skin, using quantitative real-time PCR (RT-qPCR), immunohistochemistry and bioinformatic analysis of publicly available datasets. Our data suggest that the expression of the uc.291 and of EDC genes loricrin and filaggrin (LOR, FLG) is reduced in lesional skin compared to nonlesional skin of psoriatic patients; conversely, the mRNA and protein level of ACTL6A are up-regulated. Furthermore, we provide evidence that the expression of uc.291, FLG and LOR is reduced, while ACTL6A mRNA is up-regulated, in an in vitro psoriasis-like model obtained by treating differentiated keratinocytes with interleukin 22 (IL-22). Furthermore, analysis of a publicly available dataset of human epidermal keratinocytes treated with IL-22 (GSE7216) confirmed our in vitro results. Taken together, our data reveal a novel role of uc.291 and its functional axis with ACTL6A in psoriasis disorder and a proof of concept that biological inhibition of this molecular axis could have a potential pharmacological effect against psoriasis and, in general, in skin diseases with a suppressed differentiation programme.

中文翻译：

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转录lncRNA uc.291参与过度增殖性皮肤病

uc.291 转录物通过与 ACTL6A 的物理相互作用以及随后诱导属于表皮分化复合体 (EDC) 的基因的转录来控制角质形成细胞的分化。Uc.291 还涉及低分化皮肤鳞状细胞癌的去分化表型。在这里，我们想要研究 uc.291 对过度增殖性皮肤病（例如牛皮癣）中观察到的角质形成细胞不平衡分化状态的影响。牛皮癣是一种多因素炎症性疾病，由角质形成细胞稳态改变引起。由免疫细胞浸润引发的不平衡分化状态是导致这种病理的事件之一。在目前的工作中，我们利用定量实时 PCR (RT-qPCR)、免疫组织化学和对公开数据集的生物信息学分析，探讨 uc.291 及其相互作用子 ACTL6A 在银屑病皮肤中的作用。我们的数据表明，与银屑病患者的非病变皮肤相比，uc.291 以及 EDC 基因 loricrin 和 filaggrin (LOR, FLG) 的表达在病变皮肤中降低；相反，ACTL6A的mRNA和蛋白水平上调。此外，我们提供的证据表明，在用白介素 22 (IL-22) 处理分化角质形成细胞获得的体外银屑病样模型中，uc.291、FLG 和 LOR 的表达降低，而 ACTL6A mRNA 上调。此外，对用 IL-22 (GSE7216) 处理的公开可用的人表皮角质形成细胞数据集的分析证实了我们的体外结果。总而言之，我们的数据揭示了 uc.291 及其与 ACTL6A 的功能轴在银屑病疾病中的新作用，并证明了该分子轴的生物抑制可能对银屑病以及一般皮肤病具有潜在的药理作用与抑制分化计划。