Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Institute for Computer Science and Control (SZTAKI), Eötvös Loránd Research Network, Budapest, Hungary.
Aging Cell. 2023 Oct;22(10):e13922. doi: 10.1111/acel.13922. Epub 2023 Oct 2.
Recent research revealed a rejuvenation event during early development of mice. Here, by examining epigenetic age dynamics of human embryogenesis, we tested whether a similar event exists in humans. For this purpose, we developed an epigenetic clock method, the intersection clock, that utilizes bisulfite sequencing in a way that maximizes the use of informative CpG sites with no missing clock CpG sites in test samples and applied it to human embryo development data. We observed no changes in the predicted epigenetic age between cleavage stage and blastocyst stage embryos; however, a significant decrease was observed between blastocysts and cells representing the epiblast. Additionally, by applying the intersection clock to datasets spanning pre and postimplantation, we found no significant change in the epigenetic age during preimplantation stages; however, the epigenetic age of postimplantation samples was lower compared to the preimplantation stages. We further investigated the epigenetic age of primed (representing early postimplantation) and naïve (representing preimplantation) pluripotent stem cells and observed that in all cases the epigenetic age of primed cells was significantly lower than that of naïve cells. Together, our data suggest that human embryos are rejuvenated during early embryogenesis. Hence, the rejuvenation event is conserved between the mouse and human, and it occurs around the gastrulation stage in both species. Beyond this advance, the intersection clock opens the way for other epigenetic age studies based on human bisulfite sequencing datasets as opposed to methylation arrays.
最近的研究揭示了老鼠早期发育过程中的一次年轻化事件。在这里，通过检查人类胚胎发生的表观遗传年龄动态，我们测试了在人类中是否存在类似的事件。为此，我们开发了一种表观遗传时钟方法，交集时钟，它利用亚硫酸氢盐测序的方式，最大限度地利用有信息的 CpG 位点，在测试样本中没有缺失时钟 CpG 位点。我们观察到从卵裂期到囊胚期胚胎的预测表观遗传年龄没有变化；然而，在囊胚和代表外胚层的细胞之间观察到显著下降。此外，通过将交集时钟应用于涵盖植入前和植入后的数据集，我们发现植入前阶段的表观遗传年龄没有显著变化；然而，与植入前阶段相比，植入后样本的表观遗传年龄较低。我们进一步研究了已启动（代表早期植入后）和幼稚（代表植入前）多能干细胞的表观遗传年龄，并观察到在所有情况下，已启动细胞的表观遗传年龄明显低于幼稚细胞。总之，我们的数据表明，人类胚胎在早期胚胎发生过程中会年轻化。因此，这种年轻化事件在老鼠和人类之间是保守的，并且在这两个物种中都发生在原肠胚形成阶段。除了这一进展之外，交集时钟为其他基于人类亚硫酸氢盐测序数据集的表观遗传年龄研究开辟了道路，而不是基于甲基化阵列。
