SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice
Abstract Nerve injury-induced changes in pain-associated genes contribute to genesis of neuropathic pain and comorbid anxiety. Phosphorylated CTD interacting factor-1 (PCIF1)-triggered N6, 2′-O-dimethyladenosine (m6Am) mRNA modification represents an additional layer of gene regulation. However, the...
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Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62565-5 |
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| author | Yue Huang Gan Ma Shan Xie Runa Wei Ya Liu Ying Zeng Yaxuan Zhao Qihui Wang Li Yang Huiying Huang Lingyun Hao Xiaotian Zhao Hongjun Wang Wen Shen Stanley Sau Ching Wong Jun-Li Cao Yuan-Xiang Tao Zhi-Qiang Pan |
| author_facet | Yue Huang Gan Ma Shan Xie Runa Wei Ya Liu Ying Zeng Yaxuan Zhao Qihui Wang Li Yang Huiying Huang Lingyun Hao Xiaotian Zhao Hongjun Wang Wen Shen Stanley Sau Ching Wong Jun-Li Cao Yuan-Xiang Tao Zhi-Qiang Pan |
| author_sort | Yue Huang |
| collection | DOAJ |
| description | Abstract Nerve injury-induced changes in pain-associated genes contribute to genesis of neuropathic pain and comorbid anxiety. Phosphorylated CTD interacting factor-1 (PCIF1)-triggered N6, 2′-O-dimethyladenosine (m6Am) mRNA modification represents an additional layer of gene regulation. However, the role of PCIF1 in these disorders is elusive. Here, we report PCIF1 is increased in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex in mouse with neuropathic pain and anxiety, but not inflammatory pain or anxiety alone. Serpine-1 mRNA-binding protein-1 (SERBP1) is identified as a PCIF1 cofactor, their complex mediates m6Am deposition onto mRNA. Blocking SERBP1-PCIF1 upregulation in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex abolishes m6Am gain on maf1 homolog, negative regulator of RNA polymerase III (Maf1), elevates MAF1 protein, and mitigates neuropathic pain and anxiety. Conversely, mimicking this increase adds m6Am onto Maf1, reduces MAF1, and induces comorbidity symptoms. These findings highlight the significance of m6Am in neuropathic pain-anxiety comorbidity and identify SERBP1–PCIF1 in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex as a potential therapeutic target. |
| format | Article |
| id | doaj-art-db47fe31a7c0426cacb1f1555f26a2cc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-db47fe31a7c0426cacb1f1555f26a2cc2025-08-20T03:46:15ZengNature PortfolioNature Communications2041-17232025-08-0116112210.1038/s41467-025-62565-5SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in miceYue Huang0Gan Ma1Shan Xie2Runa Wei3Ya Liu4Ying Zeng5Yaxuan Zhao6Qihui Wang7Li Yang8Huiying Huang9Lingyun Hao10Xiaotian Zhao11Hongjun Wang12Wen Shen13Stanley Sau Ching Wong14Jun-Li Cao15Yuan-Xiang Tao16Zhi-Qiang Pan17Jiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityDepartment of Anaesthesiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong KongJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityDepartment of Anesthesiology, New Jersey Medical School, Rutgers. The State University of New JerseyJiangsu Province Key Laboratory of Anesthesiology, School of Anesthesiology, Xuzhou Medical UniversityAbstract Nerve injury-induced changes in pain-associated genes contribute to genesis of neuropathic pain and comorbid anxiety. Phosphorylated CTD interacting factor-1 (PCIF1)-triggered N6, 2′-O-dimethyladenosine (m6Am) mRNA modification represents an additional layer of gene regulation. However, the role of PCIF1 in these disorders is elusive. Here, we report PCIF1 is increased in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex in mouse with neuropathic pain and anxiety, but not inflammatory pain or anxiety alone. Serpine-1 mRNA-binding protein-1 (SERBP1) is identified as a PCIF1 cofactor, their complex mediates m6Am deposition onto mRNA. Blocking SERBP1-PCIF1 upregulation in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex abolishes m6Am gain on maf1 homolog, negative regulator of RNA polymerase III (Maf1), elevates MAF1 protein, and mitigates neuropathic pain and anxiety. Conversely, mimicking this increase adds m6Am onto Maf1, reduces MAF1, and induces comorbidity symptoms. These findings highlight the significance of m6Am in neuropathic pain-anxiety comorbidity and identify SERBP1–PCIF1 in glutamatergic neurons of the hindlimb region of the primary somatosensory cortex as a potential therapeutic target.https://doi.org/10.1038/s41467-025-62565-5 |
| spellingShingle | Yue Huang Gan Ma Shan Xie Runa Wei Ya Liu Ying Zeng Yaxuan Zhao Qihui Wang Li Yang Huiying Huang Lingyun Hao Xiaotian Zhao Hongjun Wang Wen Shen Stanley Sau Ching Wong Jun-Li Cao Yuan-Xiang Tao Zhi-Qiang Pan SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice Nature Communications |
| title | SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice |
| title_full | SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice |
| title_fullStr | SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice |
| title_full_unstemmed | SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice |
| title_short | SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice |
| title_sort | serbp1 pcif1 complex controlled m6am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice |
| url | https://doi.org/10.1038/s41467-025-62565-5 |
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