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

doi:10.1186/s40104-021-00642-7

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

J Anim Sci Biotechnol. 2021 Dec 7;12(1):117. doi: 10.1186/s40104-021-00642-7.

Authors

Yue Feng^{1

2}, Yanlin Li^{1

2}, Wenduo Jiang^{1

2}, Yun Hu^{1

2}, Yimin Jia^{1

2}, Ruqian Zhao^{3

4}

Affiliations

¹ MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China.
² Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China.
³ MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China. zhaoruqian@njau.edu.cn.
⁴ Key Laboratory of Animal Physiology & Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, P. R. China. zhaoruqian@njau.edu.cn.

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 (m⁶A) 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 m⁶A modification are involved in high-energy and low protein (HELP) diet-induced FLS in laying hens, and if true, what specific m⁶A sites of lipogenic genes are modified and how GR mediates m⁶A-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 m⁶A demethylation. Concurrently, the m⁶A demethylase FTO is upregulated (P < 0.05), whereas the m⁶A reader YTHDF2 is downregulated (P < 0.05) in the liver of FLS chickens. Further analysis identifies site-specific demethylation (P < 0.05) of m⁶A 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 m⁶A metabolic genes on m⁶A-depenent post-transcriptional activation of lipogenic genes and shed new light in the molecular mechanism of FLS etiology in the chicken.

Keywords: Chicken; FTO; Fatty liver syndrome; GR; Lipogenesis; YTHDF2; m6A.