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<p>Germ cells are unique in that they tailor chromatin toward generating totipotency. Accordingly, mammalian spermatogonia, including spermatogonial stem cells that constitute the source for male gametes, acquire distinctive chromatin organization with weak insulation, but the underlying mechanism remains unknown. Here we show that STAG3, so far known to exclusively form meiotic cohesins, generates a mitotic cohesin for male germline nucleome programming in mice. Owing to its shorter chromatin residence, STAG3–cohesin attenuates topologically associating domains, rewires enhancer–promoter and Polycomb-mediated repressive interactions, and facilitates finer and more strengthened compartments, establishing a distinctive spermatogonial nucleome. Moreover, in the absence of STAG3–cohesin, spermatogonial stem cells show an impaired differentiation priming for spermatogenesis. Mitotic STAG3–cohesin is also expressed in human B cells and their malignant variations, promoting their propagation. Our findings on mitotic STAG3–cohesin elucidate a principle of male germline nucleome programming, demonstrate an unexpected mitotic role for STAG3 and might potentially improve understanding of human malignancies.</p>

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The mitotic STAG3–cohesin complex shapes male germline nucleome

  • 期刊论文

  • 发表日期：

    2025年8月25日

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  • Masahiro Nagano,
  • Bo Hu,
  • Kosuke Ogata,
  • Fumiya Umemura,
  • Yukiko Ishikura,
  • Shinnosuke Suzuki,
  • Christos C. Katsifis,
  • Masanori Yoshinaga,
  • Gabriele Litos,
  • Kota Nagasaka,
  • Wen Tang,
  • Yoshiaki Nosaka,
  • Hiromichi Sasada,
  • Hanbo Wang,
  • Daichi Kondo,
  • Yoshitaka Katou,
  • Ken Mizuta,
  • Yukihiro Yabuta,
  • Hiroshi Ohta,
  • Francisca Nathalia de Luna Vitorino,
  • Hiroshi Arima,
  • Takafumi Ichikawa,
  • Michele Gabriele,
  • Jacek Majewski,
  • Benjamin A. Garcia,
  • Osamu Takeuchi,
  • Shosei Yoshida,
  • Anders S. Hansen,
  • Jan-Michael Peters,
  • Yasushi Ishihama,
  • Mitinori Saitou

摘要

Germ cells are unique in that they tailor chromatin toward generating totipotency. Accordingly, mammalian spermatogonia, including spermatogonial stem cells that constitute the source for male gametes, acquire distinctive chromatin organization with weak insulation, but the underlying mechanism remains unknown. Here we show that STAG3, so far known to exclusively form meiotic cohesins, generates a mitotic cohesin for male germline nucleome programming in mice. Owing to its shorter chromatin residence, STAG3–cohesin attenuates topologically associating domains, rewires enhancer–promoter and Polycomb-mediated repressive interactions, and facilitates finer and more strengthened compartments, establishing a distinctive spermatogonial nucleome. Moreover, in the absence of STAG3–cohesin, spermatogonial stem cells show an impaired differentiation priming for spermatogenesis. Mitotic STAG3–cohesin is also expressed in human B cells and their malignant variations, promoting their propagation. Our findings on mitotic STAG3–cohesin elucidate a principle of male germline nucleome programming, demonstrate an unexpected mitotic role for STAG3 and might potentially improve understanding of human malignancies.