Deficiency of the palmitoyl acyltransferase ZDHHC7 modulates gene expression in mice after a mild chronic stress paradigm

Chronic stress (CS) is a debilitating condition that negatively affects body and brain. In mice, CS effects range from changes in behaviour down to the level of gene expression. These effects are partly mediated by sex and sex steroid hormones, which in turn are affected by the palmitoyl acyltransferase ZDHHC7. ZDHHC7 might modulate also the response to CS via palmitoylation of sex steroid hormone receptors and other proteins critical for neuronal structure and functions. Therefore, we aimed to investigate the role of ZDHHC7 in response to CS on different system levels in a mouse model of Zdhhc7-deficiency. Female and male Zdhhc7-knockout (KO) and -wildtype (WT) mice underwent a four-week-mild CS paradigm or non-stress control (C) condition. After C or CS, amongst other analyses, brain gene expression profiles (via mRNA-seq transcriptomics) were investigated. Analyses focused on effects of genotype (KO vs. WT) or condition (C vs. CS) separately in both sexes. Our results revealed significant effects particularly in females. Female KOs showed upregulated cortistatin expression after CS (C vs. CS: p<0.05). Zdhhc7-deficiency seemed to be related to a sex-specific stress response and may reveal genetic factors of CS-resilience in female mice.慢性应激（Chronic Stress, CS）是一种损害机体健康的衰弱性病症，会对躯体与大脑产生负面影响。在小鼠模型中，慢性应激的效应覆盖从行为改变直至基因表达水平的多个生物学层级。此类效应部分由性别与性类固醇激素介导，而性别与性类固醇激素的活性又受到棕榈酰酰基转移酶（palmitoyl acyltransferase）ZDHHC7的调控。ZDHHC7还可通过对性类固醇激素受体以及其他对神经元结构与功能至关重要的蛋白质进行棕榈酰化修饰，调节机体对慢性应激的应答反应。因此，本研究旨在构建Zdhhc7缺陷型小鼠模型，探究ZDHHC7在不同系统层级中参与慢性应激应答的作用。实验中，我们将雌性与雄性Zdhhc7敲除（knockout, KO）小鼠及野生型（wildtype, WT）小鼠分为两组，分别接受为期4周的轻度慢性应激范式处理，或非应激对照（control, C）条件。处理结束后，除开展其他相关分析外，我们还通过mRNA测序转录组学（mRNA-seq transcriptomics）对小鼠大脑的基因表达谱进行了检测。分析环节分别针对雌雄两种性别，单独聚焦于基因型（KO vs. WT）与处理条件（C vs. CS）所产生的效应。本研究结果显示，此类效应在雌性小鼠中尤为显著。与非应激对照组相比，雌性KO小鼠在经历慢性应激后，其皮质抑素（cortistatin）的表达出现显著上调（C vs. CS: p<0.05）。Zdhhc7缺陷似乎与性别特异性的应激应答密切相关，该研究或可揭示雌性小鼠慢性应激韧性的潜在遗传调控因素。