Transgenerational inheritance of epigenetic signatures at CpG islands in mice

Transgenerational epigenetic inheritance in mammals remains a subject of debate. Here we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs) in which CGIs of two metabolism related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Both the acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprograming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a first concrete step in support of transgenerational epigenetic inheritance in mammals, which may allow for a better understanding of the etiology, diagnosis and prevention of non-genetically inherited human diseases. Target enrichment-genome bisulfite sequencing (TEBS), Whole genome sequencing (WGS), Whole genome bisulfite sequencing (WGBS)