Background A growing body of evidence suggests that certain epiphenotypes can be passed across generations via both the male and female germlines of mammals. These observations have been difficult to explain owing to a global loss of the majority of known epigenetic marks present in parental chromosomes during primordial germ cell development and after fertilization. Results By integrating previously published BS-seq, DNase-seq, ATAC-seq, and RNA-seq data collected during multiple stages of primordial germ cell and pre-implantation development, we find that the methylation status of the majority of CpGs genome-wide is restored after global de-methylation, despite the fact that global CpG methylation drops to 10% in primordial germ cells and 20% in the inner cell mass of the blastocyst. We estimate the proportion of such CpGs with preserved methylation status to be 78%. Further, we find that CpGs at sites bound by transcription factors during the global re-methylation phases of germline and embryonic development remain hypomethylated across all developmental stages observed. On the other hand, CpGs at sites not bound by transcription factors during the global re-methylation phase have high methylation levels prior to global de-methylation, become de-methylated during global de-methylation, and then become re-methylated. Conclusions The results suggest that transcription factors can act as carriers of epigenetic information during germ cell and pre-implantation development by ensuring that the methylation status of CpGs is maintained. These findings provide the basis for a mechanistic description of trans-generational inheritance of epigenetic information in mammals.

中文翻译：

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通过原始生殖细胞和植入前胚胎中的转录因子防止 DNA 重新甲基化可以解释跨代表观遗传

背景 越来越多的证据表明，某些表型可以通过哺乳动物的雄性和雌性生殖系代代相传。由于在原始生殖细胞发育期间和受精后亲本染色体中存在的大多数已知表观遗传标记的整体丢失，这些观察结果难以解释。结果通过整合先前发表的在原始生殖细胞和植入前发育的多个阶段收集的 BS-seq、DNase-seq、ATAC-seq 和 RNA-seq 数据，我们发现大多数 CpGs 全基因组的甲基化状态尽管整体 CpG 甲基化在原始生殖细胞中下降到 10%，在胚泡的内细胞团中下降到 20%，但在整体去甲基化后恢复。我们估计具有保留甲基化状态的此类 CpG 的比例为 78%。此外，我们发现在生殖系和胚胎发育的全局重新甲基化阶段，转录因子结合位点的 CpG 在观察到的所有发育阶段都保持低甲基化。另一方面，在全局再甲基化阶段未受转录因子结合的位点上的 CpG 在全局去甲基化之前具有高甲基化水平，在全局去甲基化过程中去甲基化，然后再甲基化。结论 结果表明，转录因子可以通过确保维持 CpG 的甲基化状态，在生殖细胞和植入前发育过程中充当表观遗传信息的载体。