Fat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice

Caiyun Zhu,Kexin Meng,Yan Shen,Shu Liu,Rongrong Han,Lanlan Li,Qi Xu,Chen Li,Wanwan Zhu,Lingdan Xu,Renjie Liu,Jianbo Xiu,Tingfu Du

doi:10.1038/s41467-021-27044-7

Caiyun Zhu, Kexin Meng + Show 11 more

Open Access

https://doi.org/10.1038/s41467-021-27044-7

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Abstract

Post-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory. However, it is unclear whether RNA methylation plays a critical role in the pathophysiology of major depression disorder (MDD). Here, we report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus of patients with MDD and mouse models of depression. Suppressing Fto expression in the mouse hippocampus results in depression-like behaviors in adult mice, whereas overexpression of FTO expression leads to rescue of the depression-like phenotype. Epitranscriptomic profiling of N6-methyladenosine (m6A) RNA methylation in the hippocampus of Fto knockdown (KD), Fto knockout (cKO), and FTO-overexpressing (OE) mice allows us to identify adrenoceptor beta 2 (Adrb2) mRNA as a target of FTO. ADRB2 stimulation rescues the depression-like behaviors in mice and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal SIRT1 expression by c-MYC. Our findings suggest that FTO is a regulator of a mechanism underlying depression-like behavior in mice.

Highlights

Post-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory
We further measured the expression of m6A-modifying enzymes in three mouse models of depression, which have been widely employed in preclinical studies of depression, including the chronic unpredictable mild stress (UCMS), chronic restraint stress (CRS), and social defeat stress (SDS) models
We examined the mRNA expression of m6A-modifying enzymes in multiple brain regions involved in the regulation of emotions, including the prefrontal cortex (PFC), nucleus accumbens (NAC), amygdala (AMY), and hippocampus (HIP)

Summary

Introduction

Post-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory It is unclear whether RNA methylation plays a critical role in the pathophysiology of major depression disorder (MDD). We report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus of patients with MDD and mouse models of depression. ADRB2 stimulation rescues the depression-like behaviors in mice and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal SIRT1 expression by c-MYC. ADRB2 activation rescues depressive-like behaviors and spine loss caused by hippocampal FTO deficiency, and this effect is reversed by ADRB2 inhibition, suggesting the involvement of c-MYC in modulating hippocampal SIRT1 expression. It is conclusive that hippocampal FTO can be exploited to serve as a therapeutic target for depression

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