DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis

Naoki Kubo, Hidehiro Toh, Kenjiro Shirane, Takayuki Shirakawa, Hisato Kobayashi, Tetsuya Sato, Hidetoshi Sone, Yasuyuki Sato, Shin Ichi Tomizawa, Yoshinori Tsurusaki, Hiroki Shibata, Hirotomo Saitsu, Yutaka Suzuki, Naomichi Matsumoto, Mikita Suyama, Tomohiro Kono, Kazuyuki Ohbo, Hiroyuki Sasaki

Research output: Contribution to journalArticle

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Abstract

Background: In the male germline, neonatal prospermatogonia give rise to spermatogonia, which include stem cell population (undifferentiated spermatogonia) that supports continuous spermatogenesis in adults. Although the levels of DNA methyltransferases change dynamically in the neonatal and early postnatal male germ cells, detailed genome-wide DNA methylation profiles of these cells during the stem cell formation and differentiation have not been reported. Results: To understand the regulation of spermatogonial stem cell formation and differentiation, we examined the DNA methylation and gene expression dynamics of male mouse germ cells at the critical stages: neonatal prospermatogonia, and early postntal (day 7) undifferentiated and differentiating spermatogonia. We found large partially methylated domains similar to those found in cancer cells and placenta in all these germ cells, and high levels of non-CG methylation and 5-hydroxymethylcytosines in neonatal prospermatogonia. Although the global CG methylation levels were stable in early postnatal male germ cells, and despite the reported scarcity of differential methylation in the adult spermatogonial stem cells, we identified many regions showing stage-specific differential methylation in and around genes important for stem cell function and spermatogenesis. These regions contained binding sites for specific transcription factors including the SOX family members. Conclusions: Our findings show a distinctive and dynamic regulation of DNA methylation during spermatogonial stem cell formation and differentiation in the neonatal and early postnatal testes. Furthermore, we revealed a unique accumulation and distribution of non-CG methylation and 5hmC marks in neonatal prospermatogonia. These findings contrast with the reported scarcity of differential methylation in adult spermatogonial stem cell differentiation and represent a unique phase of male germ cell development.

Original languageEnglish
Article number624
JournalBMC Genomics
Volume16
Issue number1
DOIs
Publication statusPublished - Aug 20 2015

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DNA Methylation
Methylation
Testis
Cell Differentiation
Germ Cells
Stem Cells
Gene Expression
Spermatogonia
Adult Stem Cells
Spermatogenesis
SOX Transcription Factors
Methyltransferases
Placenta
Binding Sites
Genome
DNA
Population
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Genetics

Cite this

DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis. / Kubo, Naoki; Toh, Hidehiro; Shirane, Kenjiro; Shirakawa, Takayuki; Kobayashi, Hisato; Sato, Tetsuya; Sone, Hidetoshi; Sato, Yasuyuki; Tomizawa, Shin Ichi; Tsurusaki, Yoshinori; Shibata, Hiroki; Saitsu, Hirotomo; Suzuki, Yutaka; Matsumoto, Naomichi; Suyama, Mikita; Kono, Tomohiro; Ohbo, Kazuyuki; Sasaki, Hiroyuki.

In: BMC Genomics, Vol. 16, No. 1, 624, 20.08.2015.

Research output: Contribution to journalArticle

Kubo, N, Toh, H, Shirane, K, Shirakawa, T, Kobayashi, H, Sato, T, Sone, H, Sato, Y, Tomizawa, SI, Tsurusaki, Y, Shibata, H, Saitsu, H, Suzuki, Y, Matsumoto, N, Suyama, M, Kono, T, Ohbo, K & Sasaki, H 2015, 'DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis', BMC Genomics, vol. 16, no. 1, 624. https://doi.org/10.1186/s12864-015-1833-5
Kubo, Naoki ; Toh, Hidehiro ; Shirane, Kenjiro ; Shirakawa, Takayuki ; Kobayashi, Hisato ; Sato, Tetsuya ; Sone, Hidetoshi ; Sato, Yasuyuki ; Tomizawa, Shin Ichi ; Tsurusaki, Yoshinori ; Shibata, Hiroki ; Saitsu, Hirotomo ; Suzuki, Yutaka ; Matsumoto, Naomichi ; Suyama, Mikita ; Kono, Tomohiro ; Ohbo, Kazuyuki ; Sasaki, Hiroyuki. / DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis. In: BMC Genomics. 2015 ; Vol. 16, No. 1.
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abstract = "Background: In the male germline, neonatal prospermatogonia give rise to spermatogonia, which include stem cell population (undifferentiated spermatogonia) that supports continuous spermatogenesis in adults. Although the levels of DNA methyltransferases change dynamically in the neonatal and early postnatal male germ cells, detailed genome-wide DNA methylation profiles of these cells during the stem cell formation and differentiation have not been reported. Results: To understand the regulation of spermatogonial stem cell formation and differentiation, we examined the DNA methylation and gene expression dynamics of male mouse germ cells at the critical stages: neonatal prospermatogonia, and early postntal (day 7) undifferentiated and differentiating spermatogonia. We found large partially methylated domains similar to those found in cancer cells and placenta in all these germ cells, and high levels of non-CG methylation and 5-hydroxymethylcytosines in neonatal prospermatogonia. Although the global CG methylation levels were stable in early postnatal male germ cells, and despite the reported scarcity of differential methylation in the adult spermatogonial stem cells, we identified many regions showing stage-specific differential methylation in and around genes important for stem cell function and spermatogenesis. These regions contained binding sites for specific transcription factors including the SOX family members. Conclusions: Our findings show a distinctive and dynamic regulation of DNA methylation during spermatogonial stem cell formation and differentiation in the neonatal and early postnatal testes. Furthermore, we revealed a unique accumulation and distribution of non-CG methylation and 5hmC marks in neonatal prospermatogonia. These findings contrast with the reported scarcity of differential methylation in adult spermatogonial stem cell differentiation and represent a unique phase of male germ cell development.",
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AU - Kubo, Naoki

AU - Toh, Hidehiro

AU - Shirane, Kenjiro

AU - Shirakawa, Takayuki

AU - Kobayashi, Hisato

AU - Sato, Tetsuya

AU - Sone, Hidetoshi

AU - Sato, Yasuyuki

AU - Tomizawa, Shin Ichi

AU - Tsurusaki, Yoshinori

AU - Shibata, Hiroki

AU - Saitsu, Hirotomo

AU - Suzuki, Yutaka

AU - Matsumoto, Naomichi

AU - Suyama, Mikita

AU - Kono, Tomohiro

AU - Ohbo, Kazuyuki

AU - Sasaki, Hiroyuki

PY - 2015/8/20

Y1 - 2015/8/20

N2 - Background: In the male germline, neonatal prospermatogonia give rise to spermatogonia, which include stem cell population (undifferentiated spermatogonia) that supports continuous spermatogenesis in adults. Although the levels of DNA methyltransferases change dynamically in the neonatal and early postnatal male germ cells, detailed genome-wide DNA methylation profiles of these cells during the stem cell formation and differentiation have not been reported. Results: To understand the regulation of spermatogonial stem cell formation and differentiation, we examined the DNA methylation and gene expression dynamics of male mouse germ cells at the critical stages: neonatal prospermatogonia, and early postntal (day 7) undifferentiated and differentiating spermatogonia. We found large partially methylated domains similar to those found in cancer cells and placenta in all these germ cells, and high levels of non-CG methylation and 5-hydroxymethylcytosines in neonatal prospermatogonia. Although the global CG methylation levels were stable in early postnatal male germ cells, and despite the reported scarcity of differential methylation in the adult spermatogonial stem cells, we identified many regions showing stage-specific differential methylation in and around genes important for stem cell function and spermatogenesis. These regions contained binding sites for specific transcription factors including the SOX family members. Conclusions: Our findings show a distinctive and dynamic regulation of DNA methylation during spermatogonial stem cell formation and differentiation in the neonatal and early postnatal testes. Furthermore, we revealed a unique accumulation and distribution of non-CG methylation and 5hmC marks in neonatal prospermatogonia. These findings contrast with the reported scarcity of differential methylation in adult spermatogonial stem cell differentiation and represent a unique phase of male germ cell development.

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