Mechanism of METTL3 ‐mediated m6A modification in depression‐induced cognitive deficits
Open accessAbstract
Depressive disorder (DD) is associated with N6‐methyladenosine (m6A) hypermethylation. This study sought to explore the molecular mechanism of Methyltransferase‐like 3 (METTL3) in cognitive deficits of chronic unpredictable mild stress (CUMS)‐treated rats and provide novel targets for DD treatment. A DD rat model was established via CUMS treatment. Cognitive deficits were assessed via body weighing and behavioral tests. METTL3, microRNA (miR)‐221‐3p, pri‐miR‐221, GRB2‐associated binding protein 1 (Gab1) expressions in hippocampal tissues were detected via RT‐qPCR and Western blotting. m6A, DiGeorge syndrome critical region gene 8 (DGCR8)‐bound pri‐miR‐221 and pri‐miR‐221 m6A levels were measured. The binding relationship between miR‐221‐3p and Gab1 was testified by dual‐luciferase and RNA pull‐down assays. Rescue experiments were designed to confirm the role of miR‐221‐3p and Gab1. METTL3 was highly expressed in CUMS rats, and silencing METTL3 attenuated cognitive deficits of CUMS rats. METTL3‐mediated m6A modification facilitated processing and maturation of pri‐miR‐221 via DGCR8 to upregulate miR‐221‐3p. miR‐221‐3p targeted Gab1. miR‐221‐3p overexpression or Gab1 downregulation reversed the role of silencing METTL3 in CUMS rats. Overall, METTL3‐mediated m6A modification facilitated processing and maturation of pri‐miR‐221 to upregulate miR‐221‐3p and then inhibit Gab1, thereby aggravating cognitive deficits of CUMS rats.
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Upregulation of METTL3 increases miR221-3p levels, leading to Gab1s inhibition.
“In addition, this upregulation of METTL3 could increase miR221-3p levels, leading to growth factor receptor-bound protein 2 associated binding protein 1 (Gab1s) inhibition.357”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [357]
Upregulated METTL3 can aggravate cognitive impairment in rats exposed to CUMS by mediating m6A modification to promote the processing and maturation of pri-miR-221.
“Evidence from other studies suggests that upregulated METTL3 can aggravate cognitive impairment in rats exposed to CUMS by mediating m6A modification to promote the processing and maturation of pri-miR-221.”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [357]
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- Authors
- Niu, J., Wang, B., Wang, T., & Zhou, T.
- Affiliations
- Affiliated Hospital of Qingdao University (CN)
- Qingdao Mental Health Center (CN)
- Department of Geriatric Psychiatry Qingdao Mental Health Center Qingdao Shandong Province China
- Venue
- American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
- Publisher
- Wiley
- Published
- 2022-04
- Volume
- 189
- Issue
- 3-4
- Pages
- 86-99
- ISSN
- 1552-4841 (ISSN-L)
- 1552-485X
- OpenAlex
- W4280638829
- Semantic Scholar
- 9966e9ffcbba91ba3e9bfeb626d60a37c740aab1
- Cited by
- 23
- References
- 56
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 1 · 2023: 6 · 2022: 2
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- American Journal of Medical Genetics Part B Neuropsychiatric Genetics (publishedVersion)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- METTL3, N6-methyladenosine, m6A RNA methylation, depression, cognitive impairment, chronic unpredictable mild stress, miR-221-3p, DGCR8, Gab1, hippocampus, microRNA processing, RNA methylation
- MeSH terms
- Adenosine, Animals, Cognition, Depression, Methyltransferases, Phosphoproteins, Stress, Psychological, RNA-Binding Proteins, MicroRNAs, Rats
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