The Combination of DNA Methylome and Transcriptome Revealed the Intergenerational Inheritance on the Influence of Advanced Maternal Age

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.