Feng Yue, Li Yanlin, Jiang Wenduo, Hu Yun, Jia Yimin, Zhao Ruqian
MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China.
Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China.
J Anim Sci Biotechnol. 2021 Dec 7;12(1):117. doi: 10.1186/s40104-021-00642-7.
Glucocorticoid receptor (GR) mediated corticosterone-induced fatty liver syndrome (FLS) in the chicken by transactivation of Fat mass and obesity associated gene (FTO), leading to demethylation of N6-methyladenosine (mA) and post-transcriptional activation of lipogenic genes. Nutrition is considered the main cause of FLS in the modern poultry industry. Therefore, this study was aimed to investigate whether GR and mA modification are involved in high-energy and low protein (HELP) diet-induced FLS in laying hens, and if true, what specific mA sites of lipogenic genes are modified and how GR mediates mA-dependent lipogenic gene activation in HELP diet-induced FLS in the chicken.
Laying hens fed HELP diet exhibit excess (P < 0.05) lipid accumulation and lipogenic genes activation in the liver, which is associated with significantly increased (P < 0.05) GR expression that coincided with global mA demethylation. Concurrently, the mA demethylase FTO is upregulated (P < 0.05), whereas the mA reader YTHDF2 is downregulated (P < 0.05) in the liver of FLS chickens. Further analysis identifies site-specific demethylation (P < 0.05) of mA in the mRNA of lipogenic genes, including FASN, SREBP1 and SCD. Moreover, GR binding to the promoter of FTO gene is highly enriched (P < 0.05), while GR binding to the promoter of YTHDF2 gene is diminished (P < 0.05).
These results implicate a possible role of GR-mediated transcriptional regulation of mA metabolic genes on mA-depenent post-transcriptional activation of lipogenic genes and shed new light in the molecular mechanism of FLS etiology in the chicken.
糖皮质激素受体（GR）通过激活脂肪量和肥胖相关基因（FTO）介导鸡体内皮质酮诱导的脂肪肝综合征（FLS），导致N6-甲基腺苷（m⁶A）去甲基化并转录后激活脂肪生成基因。在现代家禽业中，营养被认为是FLS的主要原因。因此，本研究旨在探讨GR和m⁶A修饰是否参与高能低蛋白（HELP）日粮诱导的蛋鸡FLS，如果是，脂肪生成基因的哪些特定m⁶A位点被修饰，以及GR如何介导HELP日粮诱导的鸡FLS中m⁶A依赖的脂肪生成基因激活。
饲喂HELP日粮的蛋鸡肝脏中出现过量（P < 0.05）脂质积累和脂肪生成基因激活，这与GR表达显著增加（P < 0.05）以及整体m⁶A去甲基化相一致。同时，FLS鸡肝脏中m⁶A去甲基化酶FTO上调（P < 0.05），而m⁶A阅读器YTHDF2下调（P < 0.05）。进一步分析确定了脂肪生成基因（包括FASN、SREBP1和SCD）mRNA中m⁶A的位点特异性去甲基化（P < 0.05）。此外，GR与FTO基因启动子的结合高度富集（P < 0.05），而GR与YTHDF2基因启动子的结合减少（P < 0.05）。
这些结果表明GR介导的m⁶A代谢基因转录调控可能在m⁶A依赖的脂肪生成基因转录后激活中发挥作用，并为鸡FLS病因的分子机制提供了新的线索。
