Ontogeny-Driven rDNA Rearrangement, Methylation, and Transcription, and Paternal Influence
Ontogeny-Driven rDNA Rearrangement, Methylation, and Transcription, and Paternal Influence
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DOI：
10.1371/journal.pone.0022266
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发表时间：
2011-07-12
期刊：
影响因子：
3.7
通讯作者：
Anderson, Lucy M.
中科院分区：
文献类型：
--
作者：
Shiao, Yih-Horng;Leighty, Robert M.;Anderson, Lucy M.
基因重排发生在某些细胞类型的发育过程中，这种基因组动态受到内在和外在因素的调节，包括生长刺激剂和营养物质。这提出了一种可能性，即基因组中的这种结构变化及其随后的表观遗传修饰也可能发生在哺乳动物个体发育过程中，这一过程经历了精心安排的细胞分裂和分化。我们通过比较两个小鼠个体发育阶段和三个成年小鼠组织中rDNA多拷贝基因的单核苷酸多态定义的单倍型频率和DNA甲基化来检验这一假设。对父本暴露对遗传和表观遗传动态的可能影响也进行了研究，包括铬(III)和酸性盐溶液外在因素。用线性混合效应模型检验了产仔数、个体数和大鼠群体重复化验的变量。我们在这里报告了活跃的rDNA重排，以单倍型频率的变化为代表，发生在从第8天胚胎到6周成年小鼠的个体发育过程中，以及在不同的组织谱系中，并且可以被父亲的暴露所改变。RDNA甲基化水平也与个体发育进程相一致，并与rDNA单倍型相关。精子的甲基化水平最高，其次是肺和肝脏，并优先选择与甲基化正相关的单倍型。与肺相比，保持较低水平rDNA甲基化的肝脏表达更多的rRNA转录本。体外转录显示rRNA的表达依赖于单倍型。因此，基因组在哺乳动物个体发育过程中也是动态的，其重排可能触发表观遗传变化和随后的转录控制，这进一步受到父亲暴露的影响。
Gene rearrangement occurs during development in some cell types and this genome dynamics is modulated by intrinsic and extrinsic factors, including growth stimulants and nutrients. This raises a possibility that such structural change in the genome and its subsequent epigenetic modifications may also take place during mammalian ontogeny, a process undergoing finely orchestrated cell division and differentiation. We tested this hypothesis by comparing single nucleotide polymorphism-defined haplotype frequencies and DNA methylation of the rDNA multicopy gene between two mouse ontogenic stages and among three adult tissues of individual mice. Possible influences to the genetic and epigenetic dynamics by paternal exposures were also examined for Cr(III) and acid saline extrinsic factors. Variables derived from litters, individuals, and duplicate assays in large mouse populations were examined using linear mixed-effects model. We report here that active rDNA rearrangement, represented by changes of haplotype frequencies, arises during ontogenic progression from day 8 embryos to 6-week adult mice as well as in different tissue lineages and is modifiable by paternal exposures. The rDNA methylation levels were also altered in concordance with this ontogenic progression and were associated with rDNA haplotypes. Sperm showed highest level of methylation, followed by lungs and livers, and preferentially selected haplotypes that are positively associated with methylation. Livers, maintaining lower levels of rDNA methylation compared with lungs, expressed more rRNA transcript. In vitro transcription demonstrated haplotype-dependent rRNA expression. Thus, the genome is also dynamic during mammalian ontogeny and its rearrangement may trigger epigenetic changes and subsequent transcriptional controls, that are further influenced by paternal exposures.