LncRNA‐MEG3 Regulates Muscle Mass and Metabolic Homeostasis by Facilitating SUZ12 Liquid–Liquid Phase Separation
Abstract Skeletal muscle plays a crucial role in maintaining motor function and metabolic homeostasis, with its loss or atrophy leading to significant health consequences. Long non‐coding RNAs (lncRNAs) have emerged as key regulators in muscle biology; however, their precise roles in muscle function...
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Wiley
2025-06-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202417715 |
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| author | Yilong Yao Chao Yan Haibo Huang Shilong Wang Jiaying Li Yun Chen Xiaolu Qu Qi Bao Lingna Xu Yuanyuan Zhang Danyang Fan Xia He Yanwen Liu Yongsheng Zhang Yalan Yang Zhonglin Tang |
| author_facet | Yilong Yao Chao Yan Haibo Huang Shilong Wang Jiaying Li Yun Chen Xiaolu Qu Qi Bao Lingna Xu Yuanyuan Zhang Danyang Fan Xia He Yanwen Liu Yongsheng Zhang Yalan Yang Zhonglin Tang |
| author_sort | Yilong Yao |
| collection | DOAJ |
| description | Abstract Skeletal muscle plays a crucial role in maintaining motor function and metabolic homeostasis, with its loss or atrophy leading to significant health consequences. Long non‐coding RNAs (lncRNAs) have emerged as key regulators in muscle biology; however, their precise roles in muscle function and pathology remain to be fully elucidated. This study demonstrates that lncRNA maternally expressed gene 3 (MEG3) is preferentially expressed in slow‐twitch muscle fibers and dynamically regulated during muscle development, aging, and in the context of Duchenne muscular dystrophy (DMD). Using both loss‐ and gain‐of‐function mice models, this study shows that lncRNA‐MEG3 is critical for preserving muscle mass and function. Its depletion leads to muscle atrophy, mitochondrial dysfunction, and impaired regenerative capacity, while overexpression enhances muscle mass, increases oxidative muscle fiber content, and improves endurance. Notably, lncRNA‐MEG3 overexpression in MDX mice significantly alleviates muscle wasting and adipose tissue infiltration. Mechanistically, this study uncovers a novel interaction between lncRNA‐MEG3 and the polycomb repressive complex 2 (PRC2), where lncRNA‐MEG3 binds to SUZ12 polycomb repressive complex 2 subunit (Suz12), stabilizes PRC2, facilitates SUZ12 liquid–liquid phase separation (LLPS), and regulates the epigenetic modulation of four and a half lim domains 3 (Fhl3) and ring finger protein 128 (Rnf128). These findings not only highlight the crucial role of lncRNA‐MEG3 in muscle homeostasis but also provide new insights into lncRNA‐based therapeutic strategies for muscle‐related diseases. |
| format | Article |
| id | doaj-art-ee1e4e8b1c194e568b17a23f0ed9fdf4 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-ee1e4e8b1c194e568b17a23f0ed9fdf42025-08-20T03:31:26ZengWileyAdvanced Science2198-38442025-06-011223n/an/a10.1002/advs.202417715LncRNA‐MEG3 Regulates Muscle Mass and Metabolic Homeostasis by Facilitating SUZ12 Liquid–Liquid Phase SeparationYilong Yao0Chao Yan1Haibo Huang2Shilong Wang3Jiaying Li4Yun Chen5Xiaolu Qu6Qi Bao7Lingna Xu8Yuanyuan Zhang9Danyang Fan10Xia He11Yanwen Liu12Yongsheng Zhang13Yalan Yang14Zhonglin Tang15Shenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaBeijing Tongren Hospital Capital Medical University Beijing 100730 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaKey Laboratory of Agricultural Animal Genetics Breeding and Reproduction of Ministry of Education and Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs Huazhong Agricultural University Wuhan 430070 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaKey Laboratory of Agricultural Animal Genetics Breeding and Reproduction of Ministry of Education and Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs Huazhong Agricultural University Wuhan 430070 ChinaSchool of Animal Science and Technology Foshan University Foshan 528225 ChinaKey Laboratory of Agricultural Animal Genetics Breeding and Reproduction of Ministry of Education and Key Lab of Swine Genetics and Breeding of Ministry of Agriculture and Rural Affairs Huazhong Agricultural University Wuhan 430070 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaShenzhen Branch Guangdong Laboratory of Lingnan Modern Agriculture Key Laboratory of Livestock and Poultry Multi‐omics of MARA Agricultural Genomics Institute at Shenzhen Chinese Academy of Agricultural Sciences Shenzhen 518124 ChinaAbstract Skeletal muscle plays a crucial role in maintaining motor function and metabolic homeostasis, with its loss or atrophy leading to significant health consequences. Long non‐coding RNAs (lncRNAs) have emerged as key regulators in muscle biology; however, their precise roles in muscle function and pathology remain to be fully elucidated. This study demonstrates that lncRNA maternally expressed gene 3 (MEG3) is preferentially expressed in slow‐twitch muscle fibers and dynamically regulated during muscle development, aging, and in the context of Duchenne muscular dystrophy (DMD). Using both loss‐ and gain‐of‐function mice models, this study shows that lncRNA‐MEG3 is critical for preserving muscle mass and function. Its depletion leads to muscle atrophy, mitochondrial dysfunction, and impaired regenerative capacity, while overexpression enhances muscle mass, increases oxidative muscle fiber content, and improves endurance. Notably, lncRNA‐MEG3 overexpression in MDX mice significantly alleviates muscle wasting and adipose tissue infiltration. Mechanistically, this study uncovers a novel interaction between lncRNA‐MEG3 and the polycomb repressive complex 2 (PRC2), where lncRNA‐MEG3 binds to SUZ12 polycomb repressive complex 2 subunit (Suz12), stabilizes PRC2, facilitates SUZ12 liquid–liquid phase separation (LLPS), and regulates the epigenetic modulation of four and a half lim domains 3 (Fhl3) and ring finger protein 128 (Rnf128). These findings not only highlight the crucial role of lncRNA‐MEG3 in muscle homeostasis but also provide new insights into lncRNA‐based therapeutic strategies for muscle‐related diseases.https://doi.org/10.1002/advs.202417715fat infiltrationlncRNA‐MEG3muscle atrophyoxidative muscle fibersSUZ12 LLPS |
| spellingShingle | Yilong Yao Chao Yan Haibo Huang Shilong Wang Jiaying Li Yun Chen Xiaolu Qu Qi Bao Lingna Xu Yuanyuan Zhang Danyang Fan Xia He Yanwen Liu Yongsheng Zhang Yalan Yang Zhonglin Tang LncRNA‐MEG3 Regulates Muscle Mass and Metabolic Homeostasis by Facilitating SUZ12 Liquid–Liquid Phase Separation Advanced Science fat infiltration lncRNA‐MEG3 muscle atrophy oxidative muscle fibers SUZ12 LLPS |
| title | LncRNA‐MEG3 Regulates Muscle Mass and Metabolic Homeostasis by Facilitating SUZ12 Liquid–Liquid Phase Separation |
| title_full | LncRNA‐MEG3 Regulates Muscle Mass and Metabolic Homeostasis by Facilitating SUZ12 Liquid–Liquid Phase Separation |
| title_fullStr | LncRNA‐MEG3 Regulates Muscle Mass and Metabolic Homeostasis by Facilitating SUZ12 Liquid–Liquid Phase Separation |
| title_full_unstemmed | LncRNA‐MEG3 Regulates Muscle Mass and Metabolic Homeostasis by Facilitating SUZ12 Liquid–Liquid Phase Separation |
| title_short | LncRNA‐MEG3 Regulates Muscle Mass and Metabolic Homeostasis by Facilitating SUZ12 Liquid–Liquid Phase Separation |
| title_sort | lncrna meg3 regulates muscle mass and metabolic homeostasis by facilitating suz12 liquid liquid phase separation |
| topic | fat infiltration lncRNA‐MEG3 muscle atrophy oxidative muscle fibers SUZ12 LLPS |
| url | https://doi.org/10.1002/advs.202417715 |
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