Background:Corticotropin-releasing hormone (CRH), the major secretagogue of the hypothalamic-pituitary-adrenal (HPA) axis, is intricately intertwined with the clock genes to regulate the circadian rhythm of various body functions. N6-methyladenosine (m6A) RNA methylation is involved in the regulation of circadian rhythm, yet it remains unknown whether CRH expression and m6A modification oscillate with the clock genes in chicken hypothalamus and how the circadian rhythms change under chronic stress. Results:Chronic exposure to corticosterone (CORT) eliminated the diurnal patterns of plasma CORT and melatonin levels in the chicken. The circadian rhythms of clock genes in hippocampus, hypothalamus and pituitary are all disturbed to different extent in CORT-treated chickens. The most striking changes occur in hypothalamus in which the diurnal fluctuation of CRH mRNA is flattened, together with mRNA of other feeding-related neuropeptides. Interestingly, hypothalamic m6A level oscillates in an opposite pattern to CRH mRNA, with lowest m6A level after midnight (ZT18) corresponding to the peak of CRH mRNA before dawn (ZT22). CORT diminished the circadian rhythm of m6A methylation with significantly increased level at night. Further site-specific m6A analysis on 3'UTR of CRH mRNA indicates that higher m6A on 3'UTR of CRH mRNA coincides with lower CRH mRNA at night (ZT18 and ZT22). Conclusions:Our results indicate that chronic stress disrupts the circadian rhythms of CRH expression in hypothalamus, leading to dysfunction of HPA axis in the chicken. RNA m6A modification is involved in the regulation of circadian rhythms in chicken hypothalamus under both basal and chronic stress conditions.

Yang Yang;Wanwan Han;Aijia Zhang;Mindie Zhao;Wei Cong;Yimin Jia;Deyun Wang;Ruqian Zhao

MOE Joint International Research Laboratory of Animal Health&Food Safety,Institute of Immunology,Nanjing Agricultural University,Nanjing 210095,People's Republic of China;Key Laboratory of Animal Physiology&Biochemistry,College of Veterinary Medicine,Nanjing Agricultural University,Nanjing 210095,People's Republic of China;Institute of Traditional Chinese Veterinary Medicine,College of Veterinary Medicine,Nanjing Agricultural University,Nanjing 210095,People's Republic of China

畜牧与生物技术杂志（英文版）

[1]Yang Yang;Wanwan Han;Aijia Zhang;Mindie Zhao;Wei Cong;Yimin Jia;Deyun Wang;Ruqian Zhao-.Chronic corticosterone disrupts the circadian rhythm of CRH expression and m6A RNA methylation in the chicken hypothalamus)[J].畜牧与生物技术杂志（英文版）,2022(04):1056-1068

intricately,ZT18,ZT22

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