The barrier function of skin epidermis is crucial for our bodies to interface with the environment. Because epidermis continuously turns over throughout the lifetime, this barrier must be actively maintained by regeneration. Although several transcription factors have been established as essential activators in epidermal differentiation, it is unclear whether additional factors remain to be identified. In this study, we show that CASZ1, a multi zinc-finger transcription factor previously characterized in nonepithelial cell types, shows highest expression in skin epidermis. CASZ1 expression is upregulated during epidermal terminal differentiation. In addition, CASZ1 expression is impaired in several skin disorders with impaired barrier function, such as atopic dermatitis, psoriasis, and squamous cell carcinoma. Using transcriptome profiling coupled with RNA interference, we identified 674 differentially expressed genes with CASZ1 knockdown. Downregulated genes account for 91.2% of these differentially expressed genes and were enriched for barrier function. In organotypic epidermal regeneration, CASZ1 knockdown promoted proliferation and strongly impaired multiple terminal differentiation markers. Mechanistically, we found that CASZ1 upregulation in differentiation requires the action of both the master transcription factor, p63, and the histone acetyltransferase, p300. Taken together, our findings identify CASZ1 as an essential activator of epidermal differentiation, paving the way for future studies understanding of CASZ1 roles in skin disease.

中文翻译：

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CASZ1对于皮肤表皮终末分化至关重要

皮肤表皮的屏障功能对于我们的身体与环境的接触至关重要。由于表皮在一生中不断更新，因此必须通过再生积极维持这一屏障。尽管几种转录因子已被确定为表皮分化中必需的激活剂，但尚不清楚是否还有其他因子有待鉴定。在这项研究中，我们发现 CASZ1（一种先前在非上皮细胞类型中表征的多锌指转录因子）在皮肤表皮中表现出最高表达。 CASZ1 表达在表皮终末分化过程中上调。此外，CASZ1 表达在多种屏障功能受损的皮肤病中受损，例如特应性皮炎、牛皮癣和鳞状细胞癌。利用转录组分析与 RNA 干扰相结合，我们鉴定了 674 个 CASZ1 敲低的差异表达基因。下调基因占这些差异表达基因的 91.2%，并且富集了屏障功能。在器官型表皮再生中，CASZ1 敲除促进增殖并严重损害多个终末分化标记。从机制上讲，我们发现分化过程中 CASZ1 上调需要主转录因子 p63 和组蛋白乙酰转移酶 p300 的作用。总而言之，我们的研究结果确定 CASZ1 是表皮分化的重要激活剂，为未来研究了解 CASZ1 在皮肤病中的作用铺平了道路。