Lack of increases in methylation at three CpG-rich genomic loci in non-mitotic adult tissues during aging
Lack of increases in methylation at three CpG-rich genomic loci in non-mitotic adult tissues during aging
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DOI：
10.1186/1471-2350-8-50
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发表时间：
2007-07-31
影响因子：
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通讯作者：
Shibata, Darryl
中科院分区：
文献类型：
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作者：
Chu, Michelle W.;Siegmund, Kimberly D.;Shibata, Darryl
背景：细胞分裂发生在正常的人类发育和衰老过程中。尽管细胞分裂对人类病理学可能很重要，但一直很难推断体细胞有丝分裂的年龄(自受精卵以来的分裂总数)，因为直接计算一生的分裂数目前是不现实的。在这里，我们试图用分子时钟假说来推断相对的有丝分裂年龄。体细胞基因组可以记录它们的有丝分裂年龄，因为在更多的分裂之后，应该积累更多的复制错误。如果在不同的时间和速率分裂，有丝分裂的年龄会因细胞类型而异。方法：先前在有丝分裂的人类上皮，如肠和子宫内膜，曾观察到特定CpG位点的DNA甲基化与年龄相关的增加(称为表观遗传分子钟)。这些富含CpG的序列或“标签”开始时没有甲基化，在发育和老化过程中甲基化的潜在变化代表复制错误。为了帮助区分有丝分裂和时间相关的变化，通过对21例不同年龄的身体的心、脑、肾和肝脏进行亚硫酸氢盐测序，测量了三个不同基因(两个在常染色体上，一个在X染色体上)8-20cpg处的DNA甲基化标签模式。结果：在三个被检查的标签中，有两个在成人组织中的甲基化水平显著高于胎儿或新生儿组织。结论：在某些CpG富集区或标记上的许多体细胞甲基化的改变似乎代表复制错误，因为这种甲基化在有丝分裂上皮中随着年龄的增长而增加，而在非有丝分裂器官中则不随年龄增加。标签甲基化在不同的组织中积累的方式不同，与它们预期的系谱和有丝分裂年龄一致。尽管有必要进行进一步的研究，但这些结果表明，分裂和祖先的数量至少部分是由体细胞基因组中的表观遗传复制错误所记录的。
Background: Cell division occurs during normal human development and aging. Despite the likely importance of cell division to human pathology, it has been difficult to infer somatic cell mitotic ages (total numbers of divisions since the zygote) because direct counting of lifetime numbers of divisions is currently impractical. Here we attempt to infer relative mitotic ages with a molecular clock hypothesis. Somatic genomes may record their mitotic ages because greater numbers of replication errors should accumulate after greater numbers of divisions. Mitotic ages will vary between cell types if they divide at different times and rates.Methods: Age-related increases in DNA methylation at specific CpG sites (termed "epigenetic molecular clocks") have been previously observed in mitotic human epithelium like the intestines and endometrium. These CpG rich sequences or "tags" start unmethylated and potentially changes in methylation during development and aging represent replication errors. To help distinguish between mitotic versus time-associated changes, DNA methylation tag patterns at 8-20 CpGs within three different genes, two on autosomes and one on the X-chromosome were measured by bisulfite sequencing from heart, brain, kidney and liver of autopsies from 21 individuals of different ages.Results: Levels of DNA methylation were significantly greater in adult compared to fetal or newborn tissues for two of the three examined tags. Consistent with the relative absence of cell division in these adult tissues, there were no significant increases in tag methylation after infancy.Conclusion: Many somatic methylation changes at certain CpG rich regions or tags appear to represent replication errors because this methylation increases with chronological age in mitotic epithelium but not in non-mitotic organs. Tag methylation accumulates differently in different tissues, consistent with their expected genealogies and mitotic ages. Although further studies are necessary, these results suggest numbers of divisions and ancestry are at least partially recorded by epigenetic replication errors within somatic cell genomes.