GR-mediated transcriptional regulation of m6A metabolic genes contributes to diet-induced fatty liver in hens

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.

Automated summary

This study found that laying hens fed a HELP diet exhibited excess lipid accumulation and activation of lipogenic genes in the liver, accompanied by increased GR expression and global m(6)A demethylation. The m(6)A demethylase FTO was upregulated, while the m(6)A reader YTHDF2 was downregulated in the liver of FLS chickens. Specific demethylation of m(6)A in the mRNA of lipogenic genes was identified, with GR binding to the FTO gene promoter enriched and GR binding to the YTHDF2 gene promoter diminished.