An epigenetic switch is crucial for spermatogonia to exit the undifferentiated state toward a Kit-positive identity

Takayuki Shirakawa, Ruken Yaman-Deveci, Shin Ichi Tomizawa, Yoshito Kamizato, Kuniko Nakajima, Hidetoshi Sone, Yasuyuki Sato, Jafar Sharif, Akio Yamashita, Yuki Takada-Horisawa, Shosei Yoshida, Kiyoe Ura, Masahiro Muto, Haruhiko Koseki, Toshio Suda, Kazuyuki Ohbo

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Epigenetic modifications influence gene expression and chromatin remodeling. In embryonic pluripotent stem cells, these epigenetic modifications have been extensively characterized; by contrast, the epigenetic events of tissue-specific stem cells are poorly understood. Here, we define a new epigenetic shift that is crucial for differentiation of murine spermatogonia toward meiosis. We have exploited a property of incomplete cytokinesis, which causes male germ cells to form aligned chains of characteristic lengths, as they divide and differentiate. These chains revealed the stage of spermatogenesis, so the epigenetic differences of various stages could be characterized. Single, paired and medium chain-length spermatogonia not expressing Kit (a marker of differentiating spermatogonia) showed no expression of Dnmt3a2 and Dnmt3b (two de novo DNA methyltransferases); they also lacked the transcriptionally repressive histone modification H3K9me2. By contrast, spermatogonia consisting of ~8-16 chained cells with Kit expression dramatically upregulated Dnmt3a2/3b expression and also displayed increased H3K9me2 modification. To explore the function of these epigenetic changes in spermatogonia in vivo, the DNA methylation machinery was destabilized by ectopic Dnmt3b expression or Np95 ablation. Forced Dnmt3b expression induced expression of Kit; whereas ablation of Np95, which is essential for maintaining DNA methylation, interfered with differentiation and viability only after spermatogonia become Kit positive. These data suggest that the epigenetic status of spermatogonia shifts dramatically during the Kit-negative to Kit-positive transition. This shift might serve as a switch that determines whether spermatogonia self-renew or differentiate.

Original languageEnglish
Pages (from-to)3565-3576
Number of pages12
JournalDevelopment (Cambridge)
Volume140
Issue number17
DOIs
Publication statusPublished - 2013 Sep 1

Keywords

  • Epigenetics
  • Germ cells
  • Kit-negative identity
  • Kit-positive identity
  • Stem cell differentiation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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  • Cite this

    Shirakawa, T., Yaman-Deveci, R., Tomizawa, S. I., Kamizato, Y., Nakajima, K., Sone, H., Sato, Y., Sharif, J., Yamashita, A., Takada-Horisawa, Y., Yoshida, S., Ura, K., Muto, M., Koseki, H., Suda, T., & Ohbo, K. (2013). An epigenetic switch is crucial for spermatogonia to exit the undifferentiated state toward a Kit-positive identity. Development (Cambridge), 140(17), 3565-3576. https://doi.org/10.1242/dev.094045