Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
Clin Transl Med. 2022 Sep;12(9):e990. doi: 10.1002/ctm2.990.
The number of women delivering at advanced maternal age (AMA; > = 35) continuously increases in developed and high-income countries. Large cohort studies have associated AMA with increased risks of various pregnancy complications and adverse pregnancy outcomes, which raises great concerns about the adverse effect of AMA on the long-term health of offspring. Specific acquired characteristics of parents can be passed on to descendants through certain molecular mechanisms, yet the underlying connection between AMA-related alterations in parents and that in offspring remains largely uncharted.
We profiled the DNA methylomes of paired parental peripheral bloods and cord bloods from 20 nuclear families, including 10 AMA and 10 Young, and additional transcriptomes of 10 paired maternal peripheral bloods and cord bloods.
We revealed that AMA induced aging-like changes in DNA methylome and gene expression in both parents and offspring. The expression changes in several genes, such as SLC28A3, were highly relevant to the disorder in DNA methylation. In addition, AMA-related differentially methylated regions (DMRs) identified in mother and offspring groups showed remarkable similarities in both genomic locations and biological functions, mainly involving neuron differentiation, metabolism, and histone modification pathways. AMA-related differentially expressed genes (DEGs) shared by mother and offspring groups were highly enriched in the processes of immune cell activation and mitotic nuclear division. We further uncovered developmental-dependent dynamics for the DNA methylation of intergenerationally correlated DMRs during pre-implantation embryonic development, as well as diverse gene expression patterns during gametogenesis and early embryonic development for those common AMA-related DEGs presenting intergenerational correlation, such as CD24. Moreover, some intergenerational DEGs, typified by HTRA3, also showed the same significant alterations in AMA MII oocyte or blastocyst.
Our results reveal potential intergenerational inheritance of both AMA-related DNA methylome and transcriptome and provide new insights to understand health problems in AMA offspring.
在发达国家和高收入国家，生育年龄较大（> = 35 岁）的妇女人数持续增加。大型队列研究表明，生育年龄较大与各种妊娠并发症和不良妊娠结局的风险增加有关，这引起了人们对生育年龄较大对后代长期健康的不利影响的极大关注。父母的某些特定获得性特征可以通过某些分子机制传递给后代，但父母与后代之间与生育年龄较大相关的变化之间的潜在联系在很大程度上仍未被探索。
我们对 20 个核家庭的父母外周血和脐带血进行了 DNA 甲基化组谱分析，其中包括 10 个生育年龄较大的母亲和 10 个年轻的母亲，以及另外 10 对母亲外周血和脐带血的转录组分析。
我们发现生育年龄较大导致父母和后代的 DNA 甲基化组和基因表达出现衰老样变化。几个基因（如 SLC28A3）的表达变化与 DNA 甲基化紊乱高度相关。此外，在母亲和后代组中确定的与生育年龄较大相关的差异甲基化区域（DMR）在基因组位置和生物学功能上均具有显著的相似性，主要涉及神经元分化、代谢和组蛋白修饰途径。在母亲和后代组中共同存在的与生育年龄较大相关的差异表达基因（DEG）在免疫细胞激活和有丝分裂核分裂过程中高度富集。我们进一步揭示了在胚胎植入前发育过程中，代际相关 DMR 的 DNA 甲基化的发育依赖性动态变化，以及在配子发生和早期胚胎发育过程中，那些具有代际相关性的共同的与生育年龄较大相关的 DEG 的多样化基因表达模式，如 CD24。此外，一些代际 DEG，以 HTRA3 为代表，在生育年龄较大的 MII 卵母细胞或胚泡中也表现出相同的显著变化。
我们的研究结果揭示了生育年龄较大相关的 DNA 甲基化组和转录组的潜在代际遗传，并为理解生育年龄较大的后代的健康问题提供了新的见解。
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