METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis
Abstract Meiosis in males is a critical process that ensures complete spermatogenesis and genetic diversity. However, the key regulators involved in this process and the underlying molecular mechanisms remain unclear. Here, we report an essential role of the m6A methyltransferase METTL16 in meiotic...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202406332 |
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| author | Lisha Yin Nan Jiang Wenjing Xiong Shiyu Yang Jin Zhang Mengneng Xiong Kuan Liu Yuting Zhang Xinxin Xiong Yiqian Gui Huihui Gao Tao Li Yi Li Xiaoli Wang Youzhi Zhang Fengli Wang Shuiqiao Yuan |
| author_facet | Lisha Yin Nan Jiang Wenjing Xiong Shiyu Yang Jin Zhang Mengneng Xiong Kuan Liu Yuting Zhang Xinxin Xiong Yiqian Gui Huihui Gao Tao Li Yi Li Xiaoli Wang Youzhi Zhang Fengli Wang Shuiqiao Yuan |
| author_sort | Lisha Yin |
| collection | DOAJ |
| description | Abstract Meiosis in males is a critical process that ensures complete spermatogenesis and genetic diversity. However, the key regulators involved in this process and the underlying molecular mechanisms remain unclear. Here, we report an essential role of the m6A methyltransferase METTL16 in meiotic sex chromosome inactivation (MSCI), double‐strand break (DSB) formation, homologous recombination and SYCP1 deposition during male meiosis. METTL16 depletion results in a significantly upregulated transcriptome on sex chromosomes in pachytene spermatocytes and leads to reduced DSB formation and recombination, and increased SYCP1 depositioin during the first wave of spermatogenesis. Mechanistically, in pachytene spermatocytes, METTL16 interacts with MDC1/SCML2 to coordinate DNA damage response (DDR) and XY body epigenetic modifications that establish and maintain MSCI, and in early meiotic prophase I, METTL16 regulates DSB formation and recombination by regulating protein levels of meiosis‐related genes. Furthermore, multi‐omics analyses reveal that METTL16 interacts with translational factors and controls m6A levels in the RNAs of meiosis‐related genes (e.g., Ubr2) to regulate the expression of critical meiotic regulators. Collectively, this study identified METTL16 as a key regulator of male meiosis and demonstrated that it modulates meiosis by interacting with MSCI‐related factors and regulating m6A levels and translational efficiency (TE) of meiosis‐related genes. |
| format | Article |
| id | doaj-art-446537f084e94606aa5fc235b706dfbe |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-446537f084e94606aa5fc235b706dfbe2025-01-20T13:04:18ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202406332METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male MeiosisLisha Yin0Nan Jiang1Wenjing Xiong2Shiyu Yang3Jin Zhang4Mengneng Xiong5Kuan Liu6Yuting Zhang7Xinxin Xiong8Yiqian Gui9Huihui Gao10Tao Li11Yi Li12Xiaoli Wang13Youzhi Zhang14Fengli Wang15Shuiqiao Yuan16Institute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaLaboratory of Animal Center Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaSchool of Pharmacy Hubei University of Science and Technology Xianning 437100 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaInstitute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 ChinaAbstract Meiosis in males is a critical process that ensures complete spermatogenesis and genetic diversity. However, the key regulators involved in this process and the underlying molecular mechanisms remain unclear. Here, we report an essential role of the m6A methyltransferase METTL16 in meiotic sex chromosome inactivation (MSCI), double‐strand break (DSB) formation, homologous recombination and SYCP1 deposition during male meiosis. METTL16 depletion results in a significantly upregulated transcriptome on sex chromosomes in pachytene spermatocytes and leads to reduced DSB formation and recombination, and increased SYCP1 depositioin during the first wave of spermatogenesis. Mechanistically, in pachytene spermatocytes, METTL16 interacts with MDC1/SCML2 to coordinate DNA damage response (DDR) and XY body epigenetic modifications that establish and maintain MSCI, and in early meiotic prophase I, METTL16 regulates DSB formation and recombination by regulating protein levels of meiosis‐related genes. Furthermore, multi‐omics analyses reveal that METTL16 interacts with translational factors and controls m6A levels in the RNAs of meiosis‐related genes (e.g., Ubr2) to regulate the expression of critical meiotic regulators. Collectively, this study identified METTL16 as a key regulator of male meiosis and demonstrated that it modulates meiosis by interacting with MSCI‐related factors and regulating m6A levels and translational efficiency (TE) of meiosis‐related genes.https://doi.org/10.1002/advs.202406332DSB formationm6AmeiosisMETTL16MSCIrecombination |
| spellingShingle | Lisha Yin Nan Jiang Wenjing Xiong Shiyu Yang Jin Zhang Mengneng Xiong Kuan Liu Yuting Zhang Xinxin Xiong Yiqian Gui Huihui Gao Tao Li Yi Li Xiaoli Wang Youzhi Zhang Fengli Wang Shuiqiao Yuan METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis Advanced Science DSB formation m6A meiosis METTL16 MSCI recombination |
| title | METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis |
| title_full | METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis |
| title_fullStr | METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis |
| title_full_unstemmed | METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis |
| title_short | METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis |
| title_sort | mettl16 is required for meiotic sex chromosome inactivation and dsb formation and recombination during male meiosis |
| topic | DSB formation m6A meiosis METTL16 MSCI recombination |
| url | https://doi.org/10.1002/advs.202406332 |
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