DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis.
DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis.
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DOI：
10.1186/s12864-015-1833-5
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发表时间：
2015-08-20
期刊：
影响因子：
4.4
通讯作者：
Sasaki H
中科院分区：
文献类型：
--
作者：
Kubo N;Toh H;Shirane K;Shirakawa T;Kobayashi H;Sato T;Sone H;Sato Y;Tomizawa S;Tsurusaki Y;Shibata H;Saitsu H;Suzuki Y;Matsumoto N;Suyama M;Kono T;Ohbo K;Sasaki H
在雄性生殖细胞系中，新生精原细胞产生精原细胞，精原细胞包括支持成人连续精子发生的干细胞群（未分化精原细胞）。虽然DNA甲基转移酶的水平在新生儿和出生后早期的男性生殖细胞中动态变化，但这些细胞在干细胞形成和分化过程中的详细全基因组DNA甲基化谱尚未报道。为了了解精原干细胞形成和分化的调控，我们研究了雄性小鼠生殖细胞在关键阶段的DNA甲基化和基因表达动态：新生儿精原细胞，和出生后早期（第7天）未分化和分化的精原细胞。我们发现大的部分甲基化结构域类似于在所有这些生殖细胞中的癌细胞和胎盘中发现的那些，并且在新生儿生殖细胞中发现高水平的非CG甲基化和5-羟甲基胞嘧啶。虽然全球CG甲基化水平是稳定的，在出生后早期的男性生殖细胞，尽管缺乏差异甲基化的成人精原干细胞的报告，我们确定了许多地区显示阶段特异性差异甲基化的基因和周围的重要干细胞功能和精子发生。这些区域包含特定转录因子的结合位点，包括SOX家族成员。我们的研究结果表明，在新生儿和出生后早期睾丸精原干细胞的形成和分化过程中，DNA甲基化具有独特的动态调节作用。此外，我们揭示了一个独特的积累和分布的非CG甲基化和5 hmC标记在新生儿的睾丸原细胞。这些发现与报道的成年精原干细胞分化中差异甲基化的缺乏形成对比，代表了男性生殖细胞发育的一个独特阶段。本文的在线版本（doi：10.1186/s12864-015-1833-5）包含补充材料，可供授权用户使用。
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. 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. 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. The online version of this article (doi:10.1186/s12864-015-1833-5) contains supplementary material, which is available to authorized users.