PRC1 directs PRC2-H3K27me3 deposition to shield adult spermatogonial stem cells from differentiation

DOI DOI PDF 参考文献110件 オープンアクセス
  • Mengwen Hu
    Department of Microbiology and Molecular Genetics, University of California , Davis, Davis , CA  95616 , USA
  • Yu-Han Yeh
    Department of Microbiology and Molecular Genetics, University of California , Davis, Davis , CA  95616 , USA
  • So Maezawa
    Division of Reproductive Sciences, Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center , Cincinnati , OH  45229 , USA
  • Toshinori Nakagawa
    Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences , 5-1 Higashiyama , Myodaiji , Okazaki  444-8787 , Japan
  • Shosei Yoshida
    Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences , 5-1 Higashiyama , Myodaiji , Okazaki  444-8787 , Japan
  • Satoshi H Namekawa
    Department of Microbiology and Molecular Genetics, University of California , Davis, Davis , CA  95616 , USA

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<jats:title>Abstract</jats:title> <jats:p>Spermatogonial stem cells functionality reside in the slow-cycling and heterogeneous undifferentiated spermatogonia cell population. This pool of cells supports lifelong fertility in adult males by balancing self-renewal and differentiation to produce haploid gametes. However, the molecular mechanisms underpinning long-term stemness of undifferentiated spermatogonia during adulthood remain unclear. Here, we discover that an epigenetic regulator, Polycomb repressive complex 1 (PRC1), shields adult undifferentiated spermatogonia from differentiation, maintains slow cycling, and directs commitment to differentiation during steady-state spermatogenesis in adults. We show that PRC2-mediated H3K27me3 is an epigenetic hallmark of adult undifferentiated spermatogonia. Indeed, spermatogonial differentiation is accompanied by a global loss of H3K27me3. Disruption of PRC1 impairs global H3K27me3 deposition, leading to precocious spermatogonial differentiation. Therefore, PRC1 directs PRC2-H3K27me3 deposition to maintain the self-renewing state of undifferentiated spermatogonia. Importantly, in contrast to its role in other tissue stem cells, PRC1 negatively regulates the cell cycle to maintain slow cycling of undifferentiated spermatogonia. Our findings have implications for how epigenetic regulators can be tuned to regulate the stem cell potential, cell cycle and differentiation to ensure lifelong fertility in adult males.</jats:p>

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