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However, the key regulators involved in this process and the underlying molecular mechanisms remain unclear. Here, we report an essential role of the m<jats:sup>6<\/jats:sup>A methyltransferase METTL16 in meiotic sex chromosome inactivation (MSCI), double\u2010strand 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\u2010related genes. Furthermore, multi\u2010omics analyses reveal that METTL16 interacts with translational factors and controls m<jats:sup>6<\/jats:sup>A levels in the RNAs of meiosis\u2010related genes (e.g., <jats:italic>Ubr2<\/jats:italic>) 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\u00a0meiosis by interacting with MSCI\u2010related factors and regulating m<jats:sup>6<\/jats:sup>A levels and translational efficiency (TE) of meiosis\u2010related genes.<\/jats:p>","DOI":"10.1002\/advs.202406332","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T10:40:22Z","timestamp":1732790422000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["METTL16 is Required for Meiotic Sex Chromosome Inactivation and DSB Formation and Recombination during Male Meiosis"],"prefix":"10.1002","volume":"12","author":[{"given":"Lisha","family":"Yin","sequence":"first","affiliation":[{"name":"Institute of Reproductive Health Tongji Medical College Huazhong University of Science and Technology  Wuhan 430030 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