While we have become familiar with the link between DNA methylation and disease, an exciting epigenetic editing study now reports how DNA methylation contributes to transgenerational epigenetic inheritance in mammals and influences disease-associated traits across generations!
In their previous study, a talented team led by Juan Carlos Izpisua Belmonte at the Salk Institute for Biological Studies employed epigenetic editing tools to show the induction and maintenance of de novo methylation at a targeted CpG island (CGI) in human pluripotent stem cells. Their current follow-up study used these editing tools to next generate DNA methylation-edited mouse embryonic stem cells (mESCs) and mice to explore the in vivo transgenerational epigenetic inheritance of CGI DNA methylation in mammals. Notably, their approach also involves removing the DNA methylation-inducing (CpG-free) cassette by the PiggyBac transposase, which demonstrates the stable nature of the induced DNA methylation.
Let’s hear from Takahashi and colleagues on how epigenetic engineering tools made this CGI-based study go transgenerational:
- The targeted integration of CpG-free DNA using CRISPR/Cas9-technology induces the de novo methylation of Ankrd26 and Ldlr gene CGI in mESCs by disrupting the methylation-blocking machinery
- Microinjection of DNA methylation-edited mESCs into eight-cell stage embryos supports the development of DNA methylation-edited mice (Ankrd2 mice and Ldlr mice) that maintain the DNA methylation profile of mESCs
- The associated gene silencing also induces gene-specific phenotypic effects (obesity/hypercholesterolemia)
- Fascinatingly, the induced DNA methylation of CGIs undergoes stable inheritance by subsequent generations of Ankrd26 and Ldlr mice through both paternal and maternal germ lines until F4 and F6, respectively
- The stable inheritance of DNA methylation also supports the transmission of abnormal phenotypes across generations
- The transmission of gene silencing, a closed chromatin state, and obese phenotypes occurs until F3 in Ankrd26 mice, and the transmission of gene silencing and hypercholesterolemia occurs until F3 of Ldlr mice
- The DNA methylation levels observed at CGIs before global epigenetic reprogramming in parental primordial germ cells in vivo become reestablished in Ankrd2/Ldlr mouse embryos at the post-implantation epiblast stage, resulting in the transmission of CGI methylation to offspring
These findings put the role of DNA methylation in transgenerational epigenetic inheritance in mammals on a firm footing moving forward and suggest that further research will help to create diagnostic tools, estimate disease risk, and even prevent hereditary human disease; however, a fuller description of mechanistic details will require further experimentation.
See how CGI DNA methylation helps mammals transmit epigenetic information down the generations in Cell, February 2023.