Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Fukuroi, Shizuoka, Japan.
J Toxicol Sci. 2011 Jan;36(1):9-22. doi: 10.2131/jts.36.9.
The present study was designed to fully uncover sex and circadian modulatory effects on rat liver. Hepatic transcriptome analyses were performed at 4 hr intervals of a day-night cycle using young adult male and female rats. Sexually dimorphic genes, which were identified by a cross-sex comparison of time series data, included representative sex-predominant genes such as male- or female-predominant cytochrome P450 subfamilies (Cyp2c11, Cyp2c12, Cyp2c13, and Cyp3a2), sulfotransferases, and glutathione S-transferase Yc2. The identified sexually dimorphic genes were over-represented in the metabolism of retinols, xenobiotics, linoleic acids, or androgen and estrogen, or bile acid biosynthesis. Furthermore, transcription factor targets modeling suggested that transcription factors SP1, hepatocyte nuclear factor 4-alpha (HNF4-alpha), and signal transducer and activator of transcription 5b (STAT5b) serve as core nodes in the regulatory networks. On the other hand, Fourier transform analyses extracted universal circadian-regulated genes in both sexes. The circadian-regulated genes included clock or clock-controlled genes such as aryl hydrocarbon receptor nuclear translocator-like (Arntl), period homolog 2 (Per2), and D site albumin promoter binding protein (Dbp). The extracted cyclic genes were over-represented in major tissue activities, e.g. the urea cycle and the metabolism of amino acids, fatty acids, or glucose, indicating that the major liver functions are under circadian control. The transcription factor targets modeling suggested that transcription factors SP1, HNF4-alpha, and c-Myc proto-oncogene protein (c-MYC) serve as major hubs in the circadian-regulatory gene networks. Interestingly, transcription factors SP1 and HNF4-alpha are likely to orchestrate not only sexually dimorphic, but also circadian-regulated genes even though each criterion was rather mutually exclusive. This suggests the cross-talk between those regulations. Sexual dimorphism is likely to interact with circadian rhythmicity via overlapping gene regulatory networks on rat liver.
本研究旨在全面揭示性别和昼夜节律对大鼠肝脏的调节作用。使用年轻成年雄性和雌性大鼠，在日夜周期的 4 小时间隔内进行肝转录组分析。通过对时间序列数据进行交叉性别比较，确定了性别二态性基因，包括代表性的性别优势基因，如雄性或雌性优势细胞色素 P450 亚家族（Cyp2c11、Cyp2c12、Cyp2c13 和 Cyp3a2）、磺基转移酶和谷胱甘肽 S-转移酶 Yc2。鉴定出的性别二态性基因在视黄醇、外源性化学物质、亚油酸或雄激素和雌激素或胆汁酸生物合成的代谢中过度表达。此外，转录因子靶标建模表明，转录因子 SP1、肝细胞核因子 4-α（HNF4-α）和信号转导和转录激活因子 5b（STAT5b）作为调节网络的核心节点。另一方面，傅里叶变换分析提取了两性中普遍存在的昼夜节律调节基因。昼夜节律调节基因包括时钟或时钟控制基因，如芳香烃受体核转位蛋白样（Arntl）、周期同源物 2（Per2）和 D 位点白蛋白启动子结合蛋白（Dbp）。提取的周期性基因在主要组织活动中过度表达，例如尿素循环和氨基酸、脂肪酸或葡萄糖的代谢，表明主要的肝脏功能受昼夜节律控制。转录因子靶标建模表明，转录因子 SP1、HNF4-α 和 c-Myc 原癌基因蛋白（c-MYC）作为昼夜节律调节基因网络中的主要枢纽。有趣的是，转录因子 SP1 和 HNF4-α 可能不仅协调性别二态性，而且协调昼夜节律调节基因，尽管每个标准都相当相互排斥。这表明了这些调节之间的相互作用。性别二态性可能通过重叠的基因调节网络与昼夜节律性相互作用。
