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

Abstract

Emerging evidence has shown that stress responsivity and psychiatric diseases are associated with alterations in N 6 -methyladenosine (m 6 A) mRNA epigenetic modifications. Fat mass and obesity-associated protein (FTO) is an m 6 A 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 m 6 A 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 m 6 A-dependent transcription mechanism of stress-related neuropeptides may underlie the responses to antidepressant. Collectively, our results demonstrate that inhibiting m 6 A-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.

The role and regulatory mechanism of m6A methylation in the nervous system

“…In addition, the absence of FTO in the ventral covered area (VTA) of the midbrain was shown to increase the susceptibility of mice to stress and resistance to tricyclic antidepressants. Consistently, overexpression of FTO in the VTA significantly alleviated depression-like behavior in mice ( Wu et al, 2021 ). Moreover, FTO deficiency has been shown to reduce anxiety- and depression-like behaviors ( Sun et al, 2019 ).…”

Mechanism of METTL3‐mediated m6A modification in depression‐induced cognitive deficits

“…The behavior tests indicated that CUMS rats were presented with weakened sucrose preference, prolonged immobility time and escape latency, reduced traveling distance, shortened time to explore new objects and enter the open arms, and decreased time in the target quadrant and crossing‐platform number, indicating cognitive deficits in CUMS rats. Previous study has demonstrated that CUMS elevates m6A modification level in the DD mouse model and the abolishment of m6A modification promotes the antidepressant activity (Song, Du, Gao, & Yang, 2020; Wu et al, 2021). Accordingly, METTL3 along with m6A level was found to be increased in CUMS rats, in line with METTL3 upregulation in AD‐related cognitive deficits (Han et al, 2020; Mathoux et al, 2021).…”

“…N6‐methyladenosine (m6A) modification, the major component of mammalian RNA modifications, is associated with nervous system development and neurodegenerative diseases (Chakraborty, Tripathi, Srikumar, Raju, & Shankaranarayana Rao, 2020; Han et al, 2020). For instance, fat mass and obesity‐associated protein (FTO) as a major m6A demethylase, exerts antidepressant function and improves stress resilience via erasing m6A modification (Wu et al, 2021). Methyltransferase‐like 3 (METTL3), a well‐known m6A methyltransferase, is upregulated in Alzheimer's disease (AD) mouse models and accumulation of METTL3 catalyzes m6A modification of brain‐derived RNAs, leading to cognitive dysfunction in AD (Han et al, 2020; H. Huang, Camats‐Perna, Medeiros, Anggono, & Widagdo, 2020).…”

Adaptor protein MyD88 confers the susceptibility to stress via amplifying immune danger signals

“…For all behavioral tests, C57BL/6J mice were transported to behavioral room and adapted for at least 1 h before testing. Mice were assessed in SIT ( He et al, 2021 ), sucrose preference test (SPT) ( Luo et al, 2020 ), tail suspension test (TST) ( Zhou et al, 2019 ), forced swim test (FST) ( Deng et al, 2021 ), open field test (OFT), ( Wu et al, 2021 ) and elevated plus maze test (EPM) ( Shen et al, 2019 ) as previous reports.…”