Mechanism of <scp>METTL3</scp>‐mediated <scp>m6A</scp> modification in depression‐induced cognitive deficits

Niu, Juan; Wang, Bailing; Zhou, Tian-Tian

doi:10.1002/ajmg.b.32892

Cited by 9 publications

(4 citation statements)

References 55 publications

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“…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 Erasers. RNA modifications are removed by demethylases, allowing dynamic adjustment.…”

Section: Rna Modifications Participate In the Molecular Mechanisms Un...mentioning

confidence: 99%

Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential

Yuan,

Yang,

Rothschild

et al. 2023

Sig Transduct Target Ther

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Major depressive disorder (MDD) is a chronic, generally episodic and debilitating disease that affects an estimated 300 million people worldwide, but its pathogenesis is poorly understood. The heritability estimate of MDD is 30–40%, suggesting that genetics alone do not account for most of the risk of major depression. Another factor known to associate with MDD involves environmental stressors such as childhood adversity and recent life stress. Recent studies have emerged to show that the biological impact of environmental factors in MDD and other stress-related disorders is mediated by a variety of epigenetic modifications. These epigenetic modification alterations contribute to abnormal neuroendocrine responses, neuroplasticity impairment, neurotransmission and neuroglia dysfunction, which are involved in the pathophysiology of MDD. Furthermore, epigenetic marks have been associated with the diagnosis and treatment of MDD. The evaluation of epigenetic modifications holds promise for further understanding of the heterogeneous etiology and complex phenotypes of MDD, and may identify new therapeutic targets. Here, we review preclinical and clinical epigenetic findings, including DNA methylation, histone modification, noncoding RNA, RNA modification, and chromatin remodeling factor in MDD. In addition, we elaborate on the contribution of these epigenetic mechanisms to the pathological trait variability in depression and discuss how such mechanisms can be exploited for therapeutic purposes.

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Section: Rna Modifications Participate In the Molecular Mechanisms Un...mentioning

confidence: 99%

Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential

Yuan,

Yang,

Rothschild

et al. 2023

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…For example, major depressive disorder (MDD) is a mental health problem that is exhibited as an enormous impairment in mood, cognition, and memory and systemic inflammation, and it further harms hippocampal neurogenesis [ 41 ]. Niu et al reported that METTL3 was highly expressed in chronic unpredictable mild stress (CUMS)-induced MDD rats [ 42 ]. Further mechanic study found that METTL3-mediated m6A modification on pri-miR-221 promoted its processing and maturation that subsequently upregulated miR-221-3p expression to inhibit GRB2-associated binding protein 1 (Gab1) expression, which worsened the cognitive deficits in MDD rats [ 42 ] ( Figure 2 ).…”

Section: Mettl3 In Neuropathological Eventsmentioning

confidence: 99%

“…Niu et al reported that METTL3 was highly expressed in chronic unpredictable mild stress (CUMS)-induced MDD rats [ 42 ]. Further mechanic study found that METTL3-mediated m6A modification on pri-miR-221 promoted its processing and maturation that subsequently upregulated miR-221-3p expression to inhibit GRB2-associated binding protein 1 (Gab1) expression, which worsened the cognitive deficits in MDD rats [ 42 ] ( Figure 2 ).…”

Section: Mettl3 In Neuropathological Eventsmentioning

confidence: 99%

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

2023

Biomolecules

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Methyltransferase-like 3 (METTL3) is a typical component of N6-methyladenosine writers that exhibits methyltransferase activity and deposits methyl groups on RNA. Currently, accumulating studies have demonstrated the involvement of METTL3 in the regulation of neuro-physiological and pathological events. However, no reviews have comprehensively summarized and analyzed the roles and mechanisms of METTL3 in these events. Herein, we are focused on reviewing the roles of METTL3 in regulating normal neurophysiological (Neurogenesis, Synaptic Plasticity and Glial Plasticity, Neurodevelopment, Learning and Memory,) and neuropathological (Autism Spectrum Disorder, Major Depressive Disorder, Neurodegenerative disorders, Brain Tumors, Brain Injuries, and Other Brain Disorders) events. Our review found that although the down-regulated levels of METTL3 function through different roles and mechanisms in the nervous system, it primarily inactivates neuro-physiological events and triggers or worsens neuropathological events. In addition, our review suggests that METTL3 could be used as a diagnostic biomarker and therapeutic target in the nervous system. Collectively, our review has provided an up-to-date research outline of METTL3 in the nervous system. In addition, the regulatory network for METTL3 in the nervous system has been mapped, which could provide directions for future research, biomarkers for clinical diagnosis, and targets for disease treatment. Furthermore, this review has provided a comprehensive view, which could improve our understanding of METTL3 functions in the nervous system.

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“…For METTL3, Xu et al (2022) found that the METTL3-specific deletion in the mouse hippocampus can induce the phenotype of depression-like behaviors and spatial memory reduction [18]. In contrast, another study on METTL3 reported to significant upregulation in the hippocampus of UCMS rats and contributed to their cognitive deficits (2022) [24]. For the inconsistent findings of FTO, downregulation expression of FTO was found in the hippocampus of depressed patients and mice exhibiting depressive-like behaviors [15].…”

Section: Hypericin Upregulated the Expression Of Mettl3 And Wtapmentioning

confidence: 99%

Hypericin Ameliorates Depression-like Behaviors via Neurotrophin Signaling Pathway Mediating m6A Epitranscriptome Modification

Lei

Chen

et al. 2023

Molecules

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Hypericin, one of the major antidepressant constituents of St. John’s wort, was shown to exert antidepressant effects by affecting cerebral CYP enzymes, serotonin homeostasis, and neuroinflammatory signaling pathways. However, its exact mechanisms are unknown. Previous clinical studies reported that the mRNA modification N6-methyladenosine (m6A) interferes with the neurobiological mechanism in depressed patients, and it was also found that the antidepressant efficacy of tricyclic antidepressants (TCAs) is related to m6A modifications. Therefore, we hypothesize that the antidepressant effect of hypericin may relate to the m6A modification of epitranscriptomic regulation. We constructed a UCMS mouse depression model and found that hypericin ameliorated depressive-like behavior in UCMS mice. Molecular pharmacology experiments showed that hypericin treatment upregulated the expression of m6A-modifying enzymes METTL3 and WTAP in the hippocampi of UCMS mice. Next, we performed MeRIP-seq and RNA-seq to study m6A modifications and changes in mRNA expression on a genome-wide scale. The genome-wide m6A assay and MeRIP-qPCR results revealed that the m6A modifications of Akt3, Ntrk2, Braf, and Kidins220 mRNA were significantly altered in the hippocampi of UCMS mice after stress stimulation and were reversed by hypericin treatment. Transcriptome assays and qPCR results showed that the Camk4 and Arhgdig genes might be related to the antidepressant efficacy of hypericin. Further gene enrichment results showed that the differential genes were mainly involved in neurotrophic factor signaling pathways. In conclusion, our results show that hypericin upregulates m6A methyltransferase METTL3 and WTAP in the hippocampi of UCMS mice and stabilizes m6A modifications to exert antidepressant effects via the neurotrophin signaling pathway. This suggests that METTL3 and WTAP-mediated changes in m6A modifications may be a potential mechanism for the pathogenesis of depression and the efficacy of antidepressants, and that the neurotrophin signaling pathway plays a key role in this process.

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

Cited by 9 publications

References 55 publications

Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential

Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential

The Regulatory Network of METTL3 in the Nervous System: Diagnostic Biomarkers and Therapeutic Targets

Hypericin Ameliorates Depression-like Behaviors via Neurotrophin Signaling Pathway Mediating m6A Epitranscriptome Modification

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