N6-Methyladenosine Modification of Fatty Acid Amide Hydrolase Messenger RNA in Circular RNA STAG1–Regulated Astrocyte Dysfunction and Depressive-like Behaviors
Open accessAbstract
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.
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Overexpression of circSTAG1 significantly ameliorated depression-like behaviors and astrocyte dysfunction in the stress mice model.
“overexpression of circSTAG1 significantly ameliorated depression-like behaviors and astrocyte dysfunction in the stress mice model.296”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [296]
circSTAG1 overexpression hindered the translocation of ALKBH5 into the nucleus, leading to elevated m6A methylation of FAAH mRNA and degradation of FAAH in astrocytes followed by reduced depression-like behavior and reduced astrocyte loss.
“Huang et al. reported that circular RNA STAG (circSTAG1) overexpression hindered the translocation of ALKBH5 into the nucleus, leading to elevated m6A methylation of fatty acid amide hydrolase (FAAH) mRNA and degradation of FAAH in astrocytes followed by reduced depression-like behavior and reduced astrocyte loss.296”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [296]
circSTAG1 and circHIPK2 may be novel therapeutic targets for depression.
“These results suggest that these two circRNAs may be novel therapeutic targets for depression [16,22] (Fig. 3C & D).”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [16]
circSTAG1 and circHIPK2 function in astrocyte activation.
“Furthermore, circular STAG1 (circSTAG1) and circular HIPK2 (circHIPK2) were reported to function in astrocyte activation.”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [16]
Knockdown of circHIPK2 and overexpression of circSTAG1 have been shown to induce an inhibitory effect on the progression of depression.
“Knockdown of circHIPK2 and overexpression of circSTAG1 have been shown to induce an inhibitory effect on the progression of depression, due to the binding mechanism between circSTAG1 and human AlkB homolog 5 (ALKBH5) and the miR-9 sponge function of circHIPK2.”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [16]
mmu_circRNA002292 (DOCK4) is downregulated in mouse hippocampus.
“| 4 | mmu_circRNA002292 | DOCK4 | Mouse | | √ | Hippocampus | [16] |”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [16]
mmu_circRNA010860 (STAG1) is downregulated in human and mouse blood, hippocampus, plasma, heart, liver, spleen, lung, and kidney.
“| 1 | mmu_circRNA010860 | STAG1 | Human & | | √ | Blood, Hippocampus, Plasma, Heart, Liver, Spleen, Lung, | [16] |”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [16]
CircSTAG1 binding to ALKBH5 inhibits the translocation of cytoplasmic ALKBH5 into the nucleus and promotes up-regulation of m6A methylation of FAAH mRNA.
“(D) The binding of CircSTAG1 and ALKBH5 inhibits the translocation of cytoplasmic ALKBH5 into the nucleus, and promotes the up-regulation of m 6 A methylation of fatty acid amide hydrolase (FAAH) messenger RNA.”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [16]
This process increases degradation of FAAH in astrocytes and attenuates astrocyte dysfunction induced by CUS and corticosterone.
“This process increases degradation of FAAH in astrocytes, and finally attenuates astrocyte dysfunction induced by CUS and corticosterone.”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [16]
mmu_circRNA004239 (KALRN) is downregulated in mouse hippocampus.
“| 3 | mmu_circRNA004239 | KALRN | Mouse | | √ | Hippocampus | [16] |”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [16]
mmu_circRNA002294 (DOCK4) is downregulated in mouse hippocampus.
“| 2 | mmu_circRNA002294 | DOCK4 | Mouse | | √ | Hippocampus | [16] |”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [16]
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References 40 · Cited by 159
- Authors
- Huang, R., Zhang, Y., Bai, Y., Han, B., Ju, M., Chen, B., Yang, L., Wang, Y., Zhang, H., Zhang, H., Xie, C., Zhang, Z., & Yao, H.
- Affiliations
- Southeast University (CN)
- Henan Medical University (CN)
- Zhongda Hospital Southeast University (CN)
- Nantong University (CN)
- Corresponding author
- Yao, Honghong
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 88
- Issue
- 5
- Pages
- 392-404
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W3006906459
- Cited by
- 159
- References
- 40
- Citations by year
- 2026: 15 · 2025: 16 · 2024: 31 · 2023: 27 · 2022: 29 · 2021: 30 · 2020: 11
- FWCI
- 8.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Fundamental Research Funds for Central Universities of the Central South University (2242019K40133)
- National Key Research and Development Program of China Stem Cell and Translational Research (2017YFA0104303)
- Fundamental Research Funds for the Central Universities (2242020K40134)
- National Natural Science Foundation of China (81673410, 81973304, 81903591)
- Natural Science Foundation of Jiangsu Province (BK20191265)
- National Major Science and Technology Projects of China (2020 ZX09201015)
- National Key Research and Development Program of China
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- N6-methyladenosine, circular RNA, fatty acid amide hydrolase, ALKBH5, major depressive disorder, astrocyte dysfunction, chronic unpredictable mild stress, hippocampus, depression-like behavior, RNA methylation, corticosterone, mRNA degradation, therapeutic target
- MeSH terms
- RNA, Circular, Fatty Acid Amide Hydrolases, Adenosine, Amidohydrolases, Animals, Astrocytes, Major Depressive Disorder, Humans, Nuclear Proteins, RNA, Messenger, Mice
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