GR-mediated transcriptional regulation of m6A metabolic genes contributes to diet-induced fatty liver in hens
Yue Feng, Yanlin Li, Wenduo Jiang, Yun Hu, Yimin Jia, Ruqian Zhao
Abstract
Abstract Background 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 (m 6 A) 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 m 6 A modification are involved in high-energy and low protein (HELP) diet-induced FLS in laying hens, and if true, what specific m 6 A sites of lipogenic genes are modified and how GR mediates m 6 A-dependent lipogenic gene activation in HELP diet-induced FLS in the chicken. Results 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 m 6 A demethylation. Concurrently, the m 6 A demethylase FTO is upregulated ( P < 0.05), whereas the m 6 A reader YTHDF2 is downregulated ( P < 0.05) in the liver of FLS chickens. Further analysis identifies site-specific demethylation ( P < 0.05) of m 6 A 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). Conclusions These results implicate a possible role of GR-mediated transcriptional regulation of m 6 A metabolic genes on m 6 A-depenent post-transcriptional activation of lipogenic genes and shed new light in the molecular mechanism of FLS etiology in the chicken.