ZFP750 regulates skin lipid metabolism and cutaneous barrier

A life-essential function of the epidermis is to provide a physical barrier that prevents the loss of water and electrolytes. Essential mediators of this permeability barrier function include ceramides, cholesterol and very long chain fatty acids. Accordingly, their alteration may lead to distinct human conditions, including psoriasis or atopic dermatitis. Recently, a frameshift mutation in the human ZNF750 gene, that encodes for a zinc finger transcription factor, causing a seborrhea-like dermatitis with psoriasiform element, has brought ZNF750 as a key element for the maintenance of the epidermal tissue homeostasis. To clarify this hypothesis, with its underlying molecular mechanism, we generated a novel mouse knockout by deleting exon 2. Here, we show that genetic deletion of the mouse homolog ZFP750 results in loss of epidermal permeability barrier function. ZFP750-/- mice die shortly after birth, within 12 hours. In the stratum corneum of ZFP750-/- mice levels of ceramides, nonpolar lipids and intercellular lipid lamellae are significantly reduced. The alteration of the epidermal lipid homeostasis is directly linked to the transcriptional activity of ZFP750. Indeed, in addition to epidermal differentiation genes, ZFP750 directly and/or indirectly regulates the expression of nearly 50 crucial enzymes in the biosynthesis of ceramides, such as SPTLC1, DGAT2, SMPD3, ELOVL7 and DEGS2. Overall, our study identifies the transcription factor ZFP750 as a master regulator of lipid biosynthesis and epidermal homeostasis and may contribute to our understanding of the pathogenesis of several human skin diseases. Comparative gene expression profiling analysis of RNA-seq data of ZFP750-/- vs Wild-type mice.表皮（epidermis）的生命必需功能之一是提供物理屏障以阻止水分与电解质流失。该通透性屏障功能的关键介质包括神经酰胺（ceramides）、胆固醇（cholesterol）及超长链脂肪酸（very long chain fatty acids）。因此，这些物质的异常改变可能引发多种人类病症，包括银屑病（psoriasis）或特应性皮炎（atopic dermatitis）。近期，人类ZNF750基因中发现的移码突变（frameshift mutation）——该基因编码一种锌指转录因子（zinc finger transcription factor）——可引发伴银屑病样特征的脂溢性皮炎样皮炎，这使ZNF750成为维持表皮组织稳态（homeostasis）的关键因子。为阐明这一假说及其潜在分子机制，我们通过敲除外显子2（exon 2）构建了新型小鼠基因敲除模型。本研究证实，小鼠同源基因ZFP750的遗传缺失会导致表皮通透性屏障功能丧失。ZFP750-/-小鼠在出生后12小时内即死亡。在ZFP750-/-小鼠的角质层（stratum corneum）中，神经酰胺、非极性脂质及细胞间脂质层的水平显著降低。表皮脂质稳态的异常与ZFP750的转录活性直接相关。事实上，除表皮分化相关基因外，ZFP750可直接或间接调控近50种参与神经酰胺生物合成的关键酶的表达，例如SPTLC1、DGAT2、SMPD3、ELOVL7及DEGS2。综上，本研究鉴定转录因子ZFP750为脂质生物合成与表皮稳态的核心调控因子，可为理解多种人类皮肤疾病的发病机制提供参考。本研究对ZFP750-/-与野生型（Wild-type）小鼠的RNA测序（RNA-seq）数据开展了比较基因表达谱分析。