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

Shu Liu, Jianbo Xiu, Caiyun Zhu, Kexin Meng, Chen Li, Rongrong Han, Tingfu Du, Lanlan Li, Lingdan Xu, Renjie Liu, Wanwan Zhu, Yan Shen and Qi Xu ()
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Shu Liu: School of Basic Medicine Peking Union Medical College
Jianbo Xiu: School of Basic Medicine Peking Union Medical College
Caiyun Zhu: School of Basic Medicine Peking Union Medical College
Kexin Meng: School of Basic Medicine Peking Union Medical College
Chen Li: School of Basic Medicine Peking Union Medical College
Rongrong Han: School of Basic Medicine Peking Union Medical College
Tingfu Du: School of Basic Medicine Peking Union Medical College
Lanlan Li: School of Basic Medicine Peking Union Medical College
Lingdan Xu: School of Basic Medicine Peking Union Medical College
Renjie Liu: School of Basic Medicine Peking Union Medical College
Wanwan Zhu: School of Basic Medicine Peking Union Medical College
Yan Shen: School of Basic Medicine Peking Union Medical College
Qi Xu: School of Basic Medicine Peking Union Medical College

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27044-7

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