Increasing methylation of sperm rDNA and other repetitive elements in the aging male mammalian germline.,Aging Cell

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Increasing methylation of sperm rDNA and other repetitive elements in the aging male mammalian germline.
Aging Cell ( IF 8.0 ) Pub Date : 2020-07-01 , DOI: 10.1111/acel.13181
Ramya Potabattula ₁ , Federica Zacchini _{2,

3} , Grazyna Ewa Ptak ₂ , Marcus Dittrich _{1,

4} , Tobias Müller ₄ , Nady El Hajj _{1,

5} , Thomas Hahn ₆ , Charis Drummer _{7,

8} , Rüdiger Behr _{7,

8} , Andrea Lucas-Hahn ₉ , Heiner Niemann ₁₀ , Martin Schorsch ₆ , Thomas Haaf ₁

Affiliation

In somatic cells/tissues, methylation of ribosomal DNA (rDNA) increases with age and age‐related pathologies, which has a direct impact on the regulation of nucleolar activity and cellular metabolism. Here, we used bisulfite pyrosequencing and show that methylation of the rDNA transcription unit including upstream control element (UCE), core promoter, 18S rDNA, and 28S rDNA in human sperm also significantly increases with donor's age. This positive correlation between sperm rDNA methylation and biological age is evolutionarily conserved among mammals with widely different life spans such as humans, marmoset, bovine, and mouse. Similar to the tandemly repeated rDNA, methylation of human α‐satellite and interspersed LINE1 repeats, marmoset α‐satellite, bovine alpha‐ and testis satellite I, mouse minor and major satellite, and LINE1‐T repeats increases in the aging male germline, probably related to their sperm histone packaging. Deep bisulfite sequencing of single rDNA molecules in human sperm revealed that methylation does not only depend on donor's age, but also depend on the region and sequence context (A vs. G alleles). Both average rDNA methylation of all analyzed DNA molecules and the number of fully (>50%) methylated alleles, which are thought to be epigenetically silenced, increase with donor's age. All analyzed CpGs in the sperm rDNA transcription unit show comparable age‐related methylation changes. Unlike other epigenetic aging markers, the rDNA clock appears to operate in similar ways in germline and soma in different mammalian species. We propose that sperm rDNA methylation, directly or indirectly, influences nucleolar formation and developmental potential in the early embryo.

中文翻译：

增加衰老雄性哺乳动物生殖系中精子 rDNA 和其他重复元件的甲基化。

在体细胞/组织中，核糖体 DNA (rDNA) 的甲基化随着年龄和与年龄相关的病变而增加，这对核仁活性和细胞代谢的调节有直接影响。在这里，我们使用亚硫酸氢盐焦磷酸测序并表明人类精子中 rDNA 转录单元的甲基化，包括上游控制元件 (UCE)、核心启动子、18S rDNA 和 28S rDNA，也随着供体年龄的增加而显着增加。精子 rDNA 甲基化与生物年龄之间的这种正相关在具有广泛不同寿命的哺乳动物（例如人类、狨猴、牛和小鼠）中在进化上是保守的。类似于串联重复的 rDNA，人 α 卫星和散布的 LINE1 重复序列、狨α 卫星、牛 α 和睾丸卫星 I、小鼠小卫星和大卫星的甲基化，LINE1-T 在衰老男性生殖系中的重复增加，可能与他们的精子组蛋白包装有关。人类精子中单个 rDNA 分子的深度亚硫酸氢盐测序表明，甲基化不仅取决于供体的年龄，还取决于区域和序列背景（A 与 G 等位基因）。所有分析的 DNA 分子的平均 rDNA 甲基化和完全 (>50%) 甲基化等位基因的数量，被认为是表观遗传沉默的，随着捐赠者的年龄增加。精子 rDNA 转录单元中所有分析的 CpG 都显示出与年龄相关的甲基化变化相当。与其他表观遗传老化标记不同，rDNA 时钟似乎在不同哺乳动物物种的生殖系和体细胞中以类似的方式运作。我们建议精子 rDNA 甲基化，直接或间接，

更新日期：2020-07-01

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