PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis
Abstract Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By...
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Wiley
2024-10-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202403177 |
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| author | Wenxiang Chu Weilin Peng Yingying Lu Yishan Liu Qisheng Li Haibin Wang Liang Wang Bangke Zhang Zhixiao Liu Lin Han Hongdao Ma Haisong Yang Chaofeng Han Xuhua Lu |
| author_facet | Wenxiang Chu Weilin Peng Yingying Lu Yishan Liu Qisheng Li Haibin Wang Liang Wang Bangke Zhang Zhixiao Liu Lin Han Hongdao Ma Haisong Yang Chaofeng Han Xuhua Lu |
| author_sort | Wenxiang Chu |
| collection | DOAJ |
| description | Abstract Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF‐1α‐mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti‐resorptive therapy. |
| format | Article |
| id | doaj-art-a4048b558a2e4e61b27f26842f70dce6 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-a4048b558a2e4e61b27f26842f70dce62025-08-20T02:11:59ZengWileyAdvanced Science2198-38442024-10-011140n/an/a10.1002/advs.202403177PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During OsteoporosisWenxiang Chu0Weilin Peng1Yingying Lu2Yishan Liu3Qisheng Li4Haibin Wang5Liang Wang6Bangke Zhang7Zhixiao Liu8Lin Han9Hongdao Ma10Haisong Yang11Chaofeng Han12Xuhua Lu13Department of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaDepartment of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaObstetrics and Gynecology Hospital Fudan University Shanghai 200011 ChinaDepartment of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaDepartment of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaDepartment of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaDepartment of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaDepartment of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaHistology and Embryology Department and Shanghai Key Laboratory of Cell Engineering Naval Medical University Shanghai 200433 ChinaDepartment of Orthopaedics Third Affiliated Hospital of Naval Medical University Shanghai 201805 ChinaDepartment of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaDepartment of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaHistology and Embryology Department and Shanghai Key Laboratory of Cell Engineering Naval Medical University Shanghai 200433 ChinaDepartment of Orthopaedic Surgery Changzheng Hospital Naval Medical University Shanghai 200003 ChinaAbstract Epigenetic regulation of metabolism profoundly influences cell fate commitment. During osteoclast differentiation, the activation of RANK signaling is accompanied by metabolic reprogramming, but the epigenetic mechanisms by which RANK signaling induces this reprogramming remain elusive. By transcriptional sequence and ATAC analysis, this study identifies that activation of RANK signaling upregulates PRMT6 by epigenetic modification, triggering a metabolic switching from fatty acids oxidation toward glycolysis. Conversely, Prmt6 deficiency reverses this shift, markedly reducing HIF‐1α‐mediated glycolysis and enhancing fatty acid oxidation. Consequently, PRMT6 deficiency or inhibitor impedes osteoclast differentiation and alleviates bone loss in ovariectomized (OVX) mice. At the molecular level, Prmt6 deficiency reduces asymmetric dimethylation of H3R2 at the promoters of genes including Ppard, Acox3, and Cpt1a, enhancing genomic accessibility for fatty acid oxidation. PRMT6 thus emerges as a metabolic checkpoint, mediating metabolic switch from fatty acid oxidation to glycolysis, thereby supporting osteoclastogenesis. Unveiling PRMT6's critical role in epigenetically orchestrating metabolic shifts in osteoclastogenesis offers a promising target for anti‐resorptive therapy.https://doi.org/10.1002/advs.202403177fatty acids oxidationglycolysismetabolic reprogrammingosteoclastogenesisPRMT6 |
| spellingShingle | Wenxiang Chu Weilin Peng Yingying Lu Yishan Liu Qisheng Li Haibin Wang Liang Wang Bangke Zhang Zhixiao Liu Lin Han Hongdao Ma Haisong Yang Chaofeng Han Xuhua Lu PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis Advanced Science fatty acids oxidation glycolysis metabolic reprogramming osteoclastogenesis PRMT6 |
| title | PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis |
| title_full | PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis |
| title_fullStr | PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis |
| title_full_unstemmed | PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis |
| title_short | PRMT6 Epigenetically Drives Metabolic Switch from Fatty Acid Oxidation toward Glycolysis and Promotes Osteoclast Differentiation During Osteoporosis |
| title_sort | prmt6 epigenetically drives metabolic switch from fatty acid oxidation toward glycolysis and promotes osteoclast differentiation during osteoporosis |
| topic | fatty acids oxidation glycolysis metabolic reprogramming osteoclastogenesis PRMT6 |
| url | https://doi.org/10.1002/advs.202403177 |
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