Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice

Yuta Takahashi; Mariana Morales Valencia; Yang Yu; Yasuo Ouchi; Kazuki Takahashi; Maxim Nikolaievich Shokhirev; Kathryn Lande; April E Williams; Chiara Fresia; Masakazu Kurita; Tomoaki Hishida; Kensaku Shojima; Fumiyuki Hatanaka; Estrella Nuñez-Delicado; Concepcion Rodriguez Esteban; Juan Carlos Izpisua Belmonte

doi:10.1016/j.cell.2022.12.047

Transgenerational inheritance of acquired epigenetic signatures at CpG islands in mice

Cell. 2023 Feb 16;186(4):715-731.e19. doi: 10.1016/j.cell.2022.12.047. Epub 2023 Feb 7.

Authors

Yuta Takahashi¹, Mariana Morales Valencia¹, Yang Yu², Yasuo Ouchi³, Kazuki Takahashi¹, Maxim Nikolaievich Shokhirev⁴, Kathryn Lande⁴, April E Williams⁴, Chiara Fresia⁵, Masakazu Kurita⁶, Tomoaki Hishida⁷, Kensaku Shojima⁵, Fumiyuki Hatanaka¹, Estrella Nuñez-Delicado⁸, Concepcion Rodriguez Esteban¹, Juan Carlos Izpisua Belmonte⁹

Affiliations

¹ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA.
² Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China; Stem Cell Research Center, Peking University Third Hospital, Beijing 100191, China.
³ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA; Department of Regenerative Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan.
⁴ Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁵ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁶ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Department of Plastic, Reconstructive and Aesthetic Surgery, The University of Tokyo Hospital, Tokyo, Japan.
⁷ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Wakayama Medical University, 25-1 Shitibancho, Wakayama, Wakayama, Japan.
⁸ Universidad Católica San Antonio de Murcia (UCAM), Campus de los Jerónimos, no. 135 Guadalupe 30107, Murcia, Spain.
⁹ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA; Altos Labs, 5510 Morehouse Drive, Suite 300, San Diego, CA 92121, USA. Electronic address: [email protected].

PMID: 36754048
DOI: 10.1016/j.cell.2022.12.047

Abstract

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.

Keywords: CpG island; DNA methylation; DNA methylation-edited mice; DNA methylation-edited mouse ES cells; biological evolution; epigenome; epimutation; obesity; transgenerational epigenetic inheritance; transmission of metabolic phenotypes.

MeSH terms

Animals
CpG Islands
DNA Methylation*
Epigenesis, Genetic*
Humans
Inheritance Patterns
Mammals / genetics
Mice