Erasing m6A-dependent transcription signature of stress-sensitive genes triggers antidepressant actions

Peng-Fei Wu; Qian-Qian Han; Fu-Feng Chen; Tian-Tian Shen; Yi-Heng Li; Yu Cao; Jian-Guo Chen; Fang Wang

doi:10.1016/j.ynstr.2021.100390

Erasing m⁶A-dependent transcription signature of stress-sensitive genes triggers antidepressant actions

Neurobiol Stress. 2021 Sep 4:15:100390. doi: 10.1016/j.ynstr.2021.100390. eCollection 2021 Nov.

Authors

Peng-Fei Wu^{1

2

3

4

5}, Qian-Qian Han^{1

2}, Fu-Feng Chen^{1

2}, Tian-Tian Shen^{1

2}, Yi-Heng Li^{1

2}, Yu Cao^{1

2}, Jian-Guo Chen^{1

2

3

4

5}, Fang Wang^{1

2

3

4

5}

Affiliations

¹ Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan City, Hubei, 430030, China.
² The Research Center for Depression, Tongji Medical College, Huazhong University of Science, 430030, Wuhan, China.
³ Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan City, Hubei, 430030, China.
⁴ The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan City, Hubei, 430030, China.
⁵ Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, 430030, China.

Abstract

Emerging evidence has shown that stress responsivity and psychiatric diseases are associated with alterations in N⁶-methyladenosine (m⁶A) mRNA epigenetic modifications. Fat mass and obesity-associated protein (FTO) is an m⁶A demethylase that has been linked to increased body mass and obesity. Here, we show that tricyclic antidepressants (TCAs) with weight-gain side effects, such as imipramine and amitriptyline, directly increased FTO expression and activated its epigenetic function in the ventral tegmental area (VTA). VTA-specific genetic disruption of FTO increased stress vulnerability and abolished the antidepressant activity of TCAs, whereas erasing m⁶A modification in the VTA by FTO overexpression or cycloleucine led to significant antidepressant activity. Mechanistically, both transcriptome sequencing and quantitative PCR revealed that overexpression of FTO in the VTA decreased the transcription of stress-related neuropeptides, such as cocaine- and amphetamine-regulated transcript peptide and urocortin, in the social defeat model, which was mimicked by imipramine, suggesting an m⁶A-dependent transcription mechanism of stress-related neuropeptides may underlie the responses to antidepressant. Collectively, our results demonstrate that inhibiting m⁶A-dependent transcription of stress-related genes may work as a novel antidepressant strategy and highlight a previously unrecognized activator of FTO-dependent epigenetic function that may be used for the treatment of other neurological diseases.

Keywords: Depression; FTO; N6-methyladenosine; Stress vulnerability; Tricyclic antidepressant.