Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice

• Published in: Cell Vol. 186; no. 4; pp. 715 - 731.e19
• Main Authors: Takahashi, Yuta, Morales Valencia, Mariana, Yu, Yang, Ouchi, Yasuo, Takahashi, Kazuki, Shokhirev, Maxim Nikolaievich, Lande, Kathryn, Williams, April E., Fresia, Chiara, Kurita, Masakazu, Hishida, Tomoaki, Shojima, Kensaku, Hatanaka, Fumiyuki, Nuñez-Delicado, Estrella, Esteban, Concepcion Rodriguez, Izpisua Belmonte, Juan Carlos
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.02.2023
• Subjects: Animals; biological evolution; CpG island; CpG Islands; DNA Methylation; DNA methylation-edited mice; DNA methylation-edited mouse ES cells; Epigenesis, Genetic; epigenome; epimutation; Humans; Inheritance Patterns; Mammals - genetics; Mice; obesity; transgenerational epigenetic inheritance; transmission of metabolic phenotypes; transgenerational epigenetic inheritance; epimutation; epigenome; transmission of metabolic phenotypes; DNA methylation-edited mice; biological evolution; DNA methylation; CpG island; DNA methylation-edited mouse ES cells; obesity
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.12.047

Transgenerational epigenetic inheritance in mammals remains a debated subject. 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. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases. [Display omitted] •Establishment of targeted CGI methylation editing in mouse ES cells•DNA methylation-edited mice exhibit phenotypic alterations induced by gene silencing•Both acquired methylation and phenotypes are transmitted across multiple generations•Heritable epigenetic memory reestablishes CGI methylation at the epiblast stage Takahashi et al. demonstrate that engineered epigenetic modifications and associated phenotypes can be transmitted across multiple generations in mammals.