PMID- 32387133 OWN - NLM STAT- MEDLINE DCOM- 20210218 LR - 20220531 IS - 1873-2402 (Electronic) IS - 0006-3223 (Linking) VI - 88 IP - 5 DP - 2020 Sep 1 TI - N(6)-Methyladenosine Modification of Fatty Acid Amide Hydrolase Messenger RNA in Circular RNA STAG1-Regulated Astrocyte Dysfunction and Depressive-like Behaviors. PG - 392-404 LID - S0006-3223(20)30113-X [pii] LID - 10.1016/j.biopsych.2020.02.018 [doi] AB - BACKGROUND: N(6)-methyladenosine (m(6)A) is the most abundant epigenetic modification in eukaryotic messenger RNAs and is essential for multiple RNA processing events in physiological and pathological processes. However, precisely how m(6)A methylation is involved in major depressive disorder (MDD) is not fully understood. METHODS: Circular RNA STAG1 (circSTAG1) was screened from the hippocampus of chronic unpredictable stress-treated mice using high-throughput RNA sequencing. Microinjection of circSTAG1 lentivirus into the mouse hippocampus was used to observe the role of circSTAG1 in depression. Sucrose preference, forced swim, and tail suspension tests were performed to evaluate the depressive-like behaviors of mice. Astrocyte dysfunction was examined by GFAP immunostaining and 3D reconstruction. Methylated RNA immunoprecipitation sequence analysis was used to identify downstream targets of circSTAG1/ALKBH5 (alkB homolog 5) axis. Cell Counting Kit-8 assay was performed to evaluate astrocyte viability in vitro. RESULTS: circSTAG1 was significantly decreased in the chronic unpredictable stress-treated mouse hippocampus and in peripheral blood of patients with MDD. Overexpression of circSTAG1 notably attenuated astrocyte dysfunction and depressive-like behaviors induced by chronic unpredictable stress. Further examination indicated that overexpressed circSTAG1 captured ALKBH5 and decreased the translocation of ALKBH5 into the nucleus, leading to increased m(6)A methylation of fatty acid amide hydrolase (FAAH) messenger RNA and degradation of FAAH in astrocytes with subsequent attenuation of depressive-like behaviors and astrocyte loss induced by corticosterone in vitro. CONCLUSIONS: Our findings dissect the functional link between circSTAG1 and m(6)A methylation in the context of MDD, providing evidence that circSTAG1 may be a novel therapeutic target for MDD. CI - Copyright (c) 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved. FAU - Huang, Rongrong AU - Huang R AD - Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. FAU - Zhang, Yuan AU - Zhang Y AD - Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. FAU - Bai, Ying AU - Bai Y AD - Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. FAU - Han, Bing AU - Han B AD - Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. FAU - Ju, Minzi AU - Ju M AD - Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. FAU - Chen, Biling AU - Chen B AD - Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. FAU - Yang, Li AU - Yang L AD - Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. FAU - Wang, Yu AU - Wang Y AD - Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China. FAU - Zhang, Hongxing AU - Zhang H AD - Department of Psychology, Xinxiang Medical University, Xinxiang, Henan, China; Second Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China. FAU - Zhang, Haisan AU - Zhang H AD - Second Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China. FAU - Xie, Chunming AU - Xie C AD - Department of Neurology, Affiliated ZhongDa Hospital, Institute of Neuropsychiatry, Southeast University, Nanjing, China. FAU - Zhang, Zhijun AU - Zhang Z AD - Department of Neurology, Affiliated ZhongDa Hospital, Institute of Neuropsychiatry, Southeast University, Nanjing, China; Department of Psychology, Xinxiang Medical University, Xinxiang, Henan, China; Second Affiliated Hospital, Xinxiang Medical University, Xinxiang, Henan, China. FAU - Yao, Honghong AU - Yao H AD - Department of Pharmacology, School of Medicine, Southeast University, Nanjing, China; Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China. Electronic address: yaohh@seu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200228 PL - United States TA - Biol Psychiatry JT - Biological psychiatry JID - 0213264 RN - 0 (Nuclear Proteins) RN - 0 (RNA, Circular) RN - 0 (RNA, Messenger) RN - 0 (STAG1 protein, human) RN - CLE6G00625 (N-methyladenosine) RN - EC 3.5.- (Amidohydrolases) RN - EC 3.5.1.- (fatty-acid amide hydrolase) RN - K72T3FS567 (Adenosine) SB - IM CIN - Biol Psychiatry. 2020 Sep 1;88(5):362-364. PMID: 32792050 MH - Adenosine/analogs & derivatives MH - Amidohydrolases MH - Animals MH - *Astrocytes MH - *Depressive Disorder, Major MH - Humans MH - Mice MH - Nuclear Proteins MH - RNA, Circular MH - RNA, Messenger OTO - NOTNLM OT - ALKBH5 OT - Astrocyte OT - Depression OT - FAAH OT - N(6)-methyladenosine OT - circSTAG1 EDAT- 2020/05/11 06:00 MHDA- 2021/02/20 06:00 CRDT- 2020/05/11 06:00 PHST- 2019/08/15 00:00 [received] PHST- 2020/02/14 00:00 [revised] PHST- 2020/02/18 00:00 [accepted] PHST- 2020/05/11 06:00 [pubmed] PHST- 2021/02/20 06:00 [medline] PHST- 2020/05/11 06:00 [entrez] AID - S0006-3223(20)30113-X [pii] AID - 10.1016/j.biopsych.2020.02.018 [doi] PST - ppublish SO - Biol Psychiatry. 2020 Sep 1;88(5):392-404. doi: 10.1016/j.biopsych.2020.02.018. Epub 2020 Feb 28.