METTL3 suppresses neuropathic pain via modulating N6-methyladenosine-dependent primary miR-150 processing
Abstract Methyltransferase-like 3 (METTL3)-modulated N6-methyladenosine (m6A) was recently identified as an important epigenetic regulation type during RNA processing and contributes to multiple pathological processes. Neuropathic pain (NP) is induced by a lesion of the somatosensory nervous system,...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-00880-2 |
| _version_ | 1818491745038499840 |
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| author | Le Zhang Xin Zhao Jing Wang Yanwu Jin Moxuan Gong Yuyang Ye Peilong Li |
| author_facet | Le Zhang Xin Zhao Jing Wang Yanwu Jin Moxuan Gong Yuyang Ye Peilong Li |
| author_sort | Le Zhang |
| collection | DOAJ |
| description | Abstract Methyltransferase-like 3 (METTL3)-modulated N6-methyladenosine (m6A) was recently identified as an important epigenetic regulation type during RNA processing and contributes to multiple pathological processes. Neuropathic pain (NP) is induced by a lesion of the somatosensory nervous system, and the detailed pathways by which METTL3/m6A regulated to modulate gene dysregulation and enable NP have remained unclear. Therefore, this study investigated the function of METTL3-mediated m6A methylation on miRNA maturation, and investigated how this regulation contributes to NP progression. A rat model characterized with typical NP was established by a spared nerve-injury (SNI) method. By analyzing the expression levels of METTL3 and m6A methylation, we found that METTL3, along with m6A methylation, was dramatically downregulated in NP rats in contrast to the sham ones. Functionally, enhanced METTL3 promoted the m6A methylation in total RNAs and inhibited NP progression, whereas silencing METTL3 suppressed m6A methylation and increased NP severity. Mechanistically, METTL3 accelerated miR-150 maturation via mediating m6A methylation of primiR-150 at locus 498, cooperating with the “m6A reader” YTHDF2. Meanwhile, miR-150 could directly target brain-derived neurotrophic factor (BDNF) mRNA, and the METTL3/miR-150/BDNF regulatory pathway was finally established. Clinically, we proved that serum METTL3 mRNA was also downregulated in Shingles patients with NP, suggesting its diagnostic potential. In conclusion, we demonstrated an essential function of METTL3-regulated N6-methyladenosine during NP progression via modulating primiR-150 maturation. Serum METTL3 could effectively differentiate NP patients from healthy people, and is useful for dynamic monitoring of diseases after treatment. Therefore, the METTL3/miR-150/BDNF pathway may be a promising therapeutic target for NP patients. |
| first_indexed | 2024-12-10T17:34:59Z |
| format | Article |
| id | doaj.art-9622b1b3dc884800965c483a4004f3fb |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-12-10T17:34:59Z |
| publishDate | 2022-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-9622b1b3dc884800965c483a4004f3fb2022-12-22T01:39:34ZengNature Publishing GroupCell Death Discovery2058-77162022-02-018111410.1038/s41420-022-00880-2METTL3 suppresses neuropathic pain via modulating N6-methyladenosine-dependent primary miR-150 processingLe Zhang0Xin Zhao1Jing Wang2Yanwu Jin3Moxuan Gong4Yuyang Ye5Peilong Li6Department of Anesthesiology, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Anesthesiology, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Anesthesiology, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Anesthesiology, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Anesthesiology, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityDepartment of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong UniversityAbstract Methyltransferase-like 3 (METTL3)-modulated N6-methyladenosine (m6A) was recently identified as an important epigenetic regulation type during RNA processing and contributes to multiple pathological processes. Neuropathic pain (NP) is induced by a lesion of the somatosensory nervous system, and the detailed pathways by which METTL3/m6A regulated to modulate gene dysregulation and enable NP have remained unclear. Therefore, this study investigated the function of METTL3-mediated m6A methylation on miRNA maturation, and investigated how this regulation contributes to NP progression. A rat model characterized with typical NP was established by a spared nerve-injury (SNI) method. By analyzing the expression levels of METTL3 and m6A methylation, we found that METTL3, along with m6A methylation, was dramatically downregulated in NP rats in contrast to the sham ones. Functionally, enhanced METTL3 promoted the m6A methylation in total RNAs and inhibited NP progression, whereas silencing METTL3 suppressed m6A methylation and increased NP severity. Mechanistically, METTL3 accelerated miR-150 maturation via mediating m6A methylation of primiR-150 at locus 498, cooperating with the “m6A reader” YTHDF2. Meanwhile, miR-150 could directly target brain-derived neurotrophic factor (BDNF) mRNA, and the METTL3/miR-150/BDNF regulatory pathway was finally established. Clinically, we proved that serum METTL3 mRNA was also downregulated in Shingles patients with NP, suggesting its diagnostic potential. In conclusion, we demonstrated an essential function of METTL3-regulated N6-methyladenosine during NP progression via modulating primiR-150 maturation. Serum METTL3 could effectively differentiate NP patients from healthy people, and is useful for dynamic monitoring of diseases after treatment. Therefore, the METTL3/miR-150/BDNF pathway may be a promising therapeutic target for NP patients.https://doi.org/10.1038/s41420-022-00880-2 |
| spellingShingle | Le Zhang Xin Zhao Jing Wang Yanwu Jin Moxuan Gong Yuyang Ye Peilong Li METTL3 suppresses neuropathic pain via modulating N6-methyladenosine-dependent primary miR-150 processing Cell Death Discovery |
| title | METTL3 suppresses neuropathic pain via modulating N6-methyladenosine-dependent primary miR-150 processing |
| title_full | METTL3 suppresses neuropathic pain via modulating N6-methyladenosine-dependent primary miR-150 processing |
| title_fullStr | METTL3 suppresses neuropathic pain via modulating N6-methyladenosine-dependent primary miR-150 processing |
| title_full_unstemmed | METTL3 suppresses neuropathic pain via modulating N6-methyladenosine-dependent primary miR-150 processing |
| title_short | METTL3 suppresses neuropathic pain via modulating N6-methyladenosine-dependent primary miR-150 processing |
| title_sort | mettl3 suppresses neuropathic pain via modulating n6 methyladenosine dependent primary mir 150 processing |
| url | https://doi.org/10.1038/s41420-022-00880-2 |
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